Oxamide derivatives useful as raf-kinase inhibitors

ABSTRACT

The present invention relates to oxamide derivatives of Formula (I), the use of the compounds of Formula (I) as inhibitors of raf-kinase, the use of the compounds of Formula (I) for the manufacture of a pharmaceutical composition and a method of treatment, comprising administering said pharmaceutical composition to a patient.

The present invention-relates to oxamide derivatives, oxamidederivatives as medicaments, oxamide derivatives as inhibitors ofraf-kinase, the use of oxamide derivatives for the manufacture of apharmaceutical, a method for producing a pharmaceutical compositioncontaining said oxamide derivatives, the pharmaceutical compositionobtainable by said method and a method of treatment, comprisingadministering said pharmaceutical composition.

Protein phosphorylation is a fundamental process for the regulation ofcellular functions. The coordinated action of both protein kinases andphosphatases controls the levels of phosphorylation and, hence, theactivity of specific target proteins. One of the predominant roles ofprotein phosphorylation is in signal transduction, where extracellularsignals are amplified and propagated by a cascade of proteinphosphorylation and dephosphorylation events, e.g. in the p21^(ras)/rafpathway.

The p21^(ras) gene was discovered as an oncogene of the Harvey (rasH)and Kirsten (rasK) rat sarcoma viruses. In humans, characteristicmutations in the cellular ras gene (c-ras) have been associated withmany different types of cancers. These mutant alleles, which render Rasconstitutively active, have been shown to transform cells, such as themurine cell line NIH 3T3, in culture.

The p21^(ras) oncogene is a major contributor to the development andprogression of human solid cancers and is mutated in 30% of all humancancers (Bolton et al. (1994) Ann. Rep. Med. Chem., 29, 165-74; Bos.(1989) Cancer Res., 49, 4682-9). Oncogenic Ras mutations have beenidentified for example in lung cancer, colorectal cancer, pancreas,thyroid cancer, melanoma, bladder tumours, liver tumour, kidney tumor,dermatological tumours and haematological tumors (Ddjei et al. (2001),J. Natl. Cancer Inst. 93(14), 1062-74; Midgley, R. S. and Kerr, D. J.(2002) Critical Rev. Onc/ hematol 44, 109-120; Downward, J. (2003),Nature reviews 3, 11-22). In its normal, unmutated form, the ras proteinis a key element of the signal transduction cascade directed by growthfactor receptors in almost all tissues (Avruch et al. (1994) TrendsBiochem. Sci., 19, 279-83).

Biochemically, ras is a guanine nucleotide binding protein, and cyclingbetween a GTP-bound activated and a GDP-bound resting form is strictlycontrolled by ras endogenous GTPase activity and other regulatoryproteins. The ras gene product binds to guanine triphosphate (GTP) andguanine diphosphate (GDP) and hydrolyzes GTP to GDP. It is the GTP-boundstate of Ras that is active. In the ras mutants in cancer cells, theendogenous GTPase activity is alleviated and, therefore, the proteindelivers constitutive growth signals to downstream effectors such as theenzyme raf kinase. This leads to the cancerous growth of the cells whichcarry these mutants (Magnuson et al. (1994) Semin. Cancer Biol., 5,247-53). The ras proto-oncogene requires a functionally intact c-raf1proto-oncogene in order to transduce growth and differentiation signalsinitiated by receptor and non-receptor tyrosine kinases in highereukaryotes.

Activated Ras is necessary for the activation of the c-raf1proto-oncogene, but the biochemical steps through which Ras activatesthe Raf-1 protein (Ser/Thr) kinase are now well characterized. It hasbeen shown that inhibiting the effect of active ras by inhibiting theraf kinase signaling pathway by administration of deactivatingantibodies to raf kinase or by co-expression of dominant negative rafkinase or dominant negative MEK (MAPKK), the substrate of raf kinase,leads to the reversion of transformed cells to the normal growthphenotype see: Daum et al. (1994) Trends Biochem. Sci., 19, 474-80;Fridman et al. (1994) J Biol. Chem., 269, 30105-8. Kolch et al. (1991)Nature, 349, 426-28) and for review Weinstein-Oppenheimer et al. Pharm.& Therap. (2000), 88, 229-279. Similarly, inhibition of raf kinase (byantisense oligodeoxynucleotides) has been correlated in vitro and invivo with inhibition of the growth of a variety of human tumor types(Monia et al., Nat. Med. 1996, 2, 668-75; Geiger et al. (1997), Clin.Cancer Res. 3(7): 1179-85; Lau et al. (2002), Antisense Nucl. Acid. DrugDev. 12(1): 11-20; McPhillips et al. (2001), Br. J. Cancer 85(11):1753-8).

Raf serine- and threonine-specific protein kinases are cytosolic enzymesthat stimulate cell growth in a variety of cell systems (Rapp, U. R., etal. (1988) in The oncogene handbook; T. Curran, E. P. Reddy, and A.Skalka (ed.) Elsevier Science Publishers; The Netherlands, pp. 213-253;Rapp, U. R., et al. (1988) Cold Spring Harbor Sym. Quant. Biol.53:173-184; Rapp, U. R., et al. (1990) Inv Curr. Top. Microbiol. Amunol.Potter and Melchers (eds), Berlin, Springer-Verlag 166:129-139).

Three isozymes have been characterized:

c-Raf (also named Raf-1, c-raf-1 or c-raf1) (Bonner, T. I., et al.(1986) Nucleic Acids Res. 14:1009-1015). A-Raf (Beck, T. W., et al.(1987) Nucleic Acids Res. 15:595-609), and B-Raf (Qkawa, S., et al.(1998) Mol. Cell. Biol. 8:2651-2654; Sithanandam, G. et a. (1990)Oncogene:1775). These enzymes differ in their expression in varioustissues. Raf-1 is expressed in all organs and in all cell lines thathave been examined, and A- and B-Raf are expressed in urogenital andbrain tissues, respectively (Storm, S. M. (1990) Oncogene 5:345-351).

Raf genes are proto-oncogenes: they can initiate malignanttransformation of cells when expressed in specifically altered forms.Genetic changes that lead to oncogenic activation generate aconstitutively active protein kinase by removal or interference with anN-terminal negative regulatory domain of the protein (Heidecker, G., etal. (1990) Mol. Cell. Biol. 10:2503-2512; Rapp, U. R., et al. (1987) inOncogenes and cancer S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada,K. Toyoshima, and P. K. Vogt (ed). Japan Scientific Press, Tokyo).Microinjection into NIH 3T3 cells of oncogenically activated but notwild-type versions of the Raf-protein prepared with Escherichia coliexpression vectors results in morphological transformation andstimulates DNA synthesis (Rapp, U. R., et al. (1987) in Oncogenes andcancer; S. A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima,and P. K. Vogt (ed.) Japan Scientific Press, Tokyo; Smith, M. R., et al(1990) Mol. Cell. Biol. 10:3828-3833). Activating mutants of B-Raf havebeen identified in a wide range of human cancers e.g. colon, ovarien,melanomas and sarcomas (Davies, H., et al. (2002), Nature 417 949-945.Published online Jun. 9, 2002, 10.1038/nature00766). The preponderantmutation is a single phosphomimetic substitution in the kinaseactivation domain (V599E), leading to constitutive kinase activity andtransformation of NIH3T3 cells.

Thus, activated Raf-1 is an intracellular activator of cell growth.Raf-1 protein serine kinase in a candidate downstream effector ofmitogen signal transduction, since Raf oncogenes overcome growth arrestresulting from a block of cellular ras activity due either to a cellularmutation (ras revertant cells) or microinjection of anti-ras antibodies(Rapp, U. R., et al. (1988) in The Oncogene Handbook, T. Curran, E. P.Reddy, and A. Skalka (ed.), Elsevier Science Publishers; TheNetherlands, pp. 213-253; Smith, M. R., et al. (1986) Nature (London)320:540-543).

c-Raf function is required for transformation by a variety ofmembrane-bound oncogenes and for growth stimulation by mitogenscontained in serums (Smith, M. R., et al. (1986) Nature (London)320:540-543). Raf-1 protein serine kinase activity is regulated bymitogens via phosphorylation (Morrison, D. K., et al. (1989) Cell58:648-657), which also effects sub cellular distribution (Olah, Z., etal. (1991) Exp. Brain Res. 84:403; Rapp, U. R., et al. (1988) ColdSpring Harbor Sym. Quant. Biol. 53:173-184. Raf-1 activating growthfactors include platelet-derived growth factor (PDGF) (Morrison, D. K.,et al. (1988) Proc. Natl. Acad. Sci. USA 85:8855-8859),colony-stimulating factor (Baccarini, M., et al. (1990) EMBO J.9:3649-3657), insulin (Blackshear, P. J., et al. (1990) J. Biol. Chem.265:12115-12118), epidermal growth factor (EGF) (Morrison, R. K., et al.(1988) Proc. Natl. Acad. Sci. USA 85:8855-8859), interleukin 2 (Turner,B. C., et al (1991) Proc. Natl. Acad. Sci. USA 88:1227), and interleukin3 and granulocytemacrophage colony-stimulating factor (Carroll, M. P.,et al (1990) J. Biol. Chem. 265:19812-19817).

Upon mitogen treatment of cells, the transiently activated Raf-1 proteinserine kinase translocates to the perinuclear area and the nucleus(Olah, Z., et al. (1991) Exp. Brain Res. 84:403; Rapp, U. R., et al.(1988) Cold Spring Habor Sym. Quant. Biol. 53:173-184). Cells containingactivated Raf are altered in their pattern of gene expression(Heidecker, G., et al. (1989) in Genes and signal transduction inmultistage carcinogenesis, N. Colburn (ed.), Marcel Dekker, Inc., NewYork, pp. 339-374), and Raf oncogenes activate transcription fromAp-I/PEA3-dependent promoters in transient transfection assays (Jamal,S., et al (1990) Science 344:463-466; Kaibuchi, K., et al (1989) J.Biol. Chem. 264:20855-20858; Wasylyk, C., et al. (1989) Mol. Cell. Biol.9:2247-2250).

There are at least two independent pathways for Raf-1 activation byextracellular mitogens: one involving protein kinase C (KC) and a secondinitiated by protein tyrosine kinases (Blackshear, P. J., et al. (1990)J. Biol. Chem. 265:12131-12134; Kovacina, K. S., et al (1990) J. Biol.Chem. 265:12115-12118; Morrison, D. K., et al. (1988) Proc. Natl. Acad.Sci. USA 85:8855-8859; Siegel, J. N., et al (1990) J. Biol. Chem.265:18472-18480; Turner, B. C., et al (1991) Proc. Natl. Acad. Sci. USA88:1227). In either case, activation involves Raf-1 proteinphosphorylation. Raf-1 phosphorylation may be a consequence of a kinasecascade amplified by autophosphorylation or may be caused entirely byautophosphorylation initiated by binding of a putative activating ligandto the Raf-1 regulatory domain, analogous to PKC activation bydiacylglycerol (Nishizuka, Y. (1986) Science 233:305-312).

The process of angiogenesis is the development of new blood vessels,generally capillaries, from pre-existing vasculature. Angiogenesis isdefined as involving (i) activation of endothelial cells; (ii) increasedvascular permeability; (iii) subsequent dissolution of the basementmembrane and extravisation of plasma components leading to formation ofa provisional fibrin gel extracellular matrix; (iv) proliferation andmobilization of endothelial cells; (v) reorganization of mobilizedendothelial cells to form functional capillaries; (vi) capillary loopformation; and (vii) deposition of basement membrane and recruitment ofperivascular cells to newly formed vessels.

Normal angiogenesis is activated during tissue growth, from embryonicdevelopment through maturity, and then enters a period of relativequiescence during adulthood. Normal angiogensesis is also activatedduring wound healing, and at certain stages of the female reproductivecycle. Inappropriate or pathological angiogenesis has been associatedwith several disease states including various retinopathies; ischemicdisease; atherosclerosis; chronic inflammatory disorders; rheumatoidarthritis, and cancer. The role of angiogenesis in disease states isdiscussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:5466; Shawver et al, DOT Vol. 2, No. 2 Feb. 1997; Folkmann, 1995, NatureMedicine 1:27-31.

In cancer the growth of solid tumors has been shown to be angiogenesisdependent. (See Folkmann, J., J. Nat'l. Cancer Inst., 1990, 82, 4-6.)Consequently, the targeting of pro-angiogenic pathways is a strategybeing widely pursued in order to provide new therapeutics in these areasof great, unmet medical need.

Raf is involved in angiogenic processes. Endothelial growth factors(e.g. vascular endothelial growth factor VEGF or basic fibroblast growthfactor bFGF) activates receptor tyrosine kinases (e.g. VEGFR-2) andsignal through the Ras/Raf/Mek/Erk kinase cascade and protectsendothelial cells from apoptosis (Alavi et al. (2003), Science 301,94-96; Hood, J. D. et al. (2002), Science 296, 2404; Mikula, M. et al.(2001), EMBO J. 20, 1952; Hauser, M. et al. (2001), EMBO J. 20, 1940;Wojnowski et al. (1997), Nature Genet. 16, 293). Activation of VEGFR-2by VEGF is a critical step in the signal transduction pathway thatinitiates tumor angiogenesis. VEGF expression may be constitutive totumor cells and can also be upregulated in response to certain stimuli.One such stimuli is hypoxia, where VEGF expression is upregulated inboth tumor and associated host tissues. The VEGF ligand activatesVEGFR-2 by binding with its extracellular VEGF binding site. This leadsto receptor dimerization of VEGFRs and autophosphorylation of tyrosineresidues at the intracellular kinase domain of VEGFR-2. The kinasedomain operates to transfer a phosphate from ATP to the tyrosineresidues, thus providing binding sites for signaling proteins downstreamof VEGFR-2 leading ultimately to initiation of angiogenesis (McMahon,G., The Oncologist, Vol. 5, No. 90001, 3-10, April 2000).

Mice with a targeted disruption in the Braf gene die of vascular defectsduring development (Wojnowski, L. et al. 1997, Nature genetics 16, page293-296). These mice show defects in the formation of the vascularsystem and in angiogenesis e.g. enlarged blood vessels and increasedapoptotic death of differentiated endothelial cells.

For the identification of a signal transduction pathway and thedetection of cross talks with other signaling pathways suitable modelsor model systems have been generated by various scientists, for examplecell culture models (e.g. Khwaja et al., EMBO, 1997, 16, 2783-93) andtransgenic animal models (e.g. White et al., Oncogene, 2001, 20,7064-7072). For the examintion of particular steps in the signaltransduction cascade, interfering compounds can be used for signalmodulation (e.g. Stephens et al., Biochemical J., 2000, 351, 95-105).The compounds according to the invention may also be useful as reagentsfor the examination of kinase dependent signal transduction pathways inanimal and/or cell culture models or any of the clinical disorderslisted throughout this application.

The measurement of kinase activity is a well known technique feasiblefor each person skilled in the art. Generic test systems for kinaseactivity detection with substrates, for example histone (e.g. Alessi etal., FEBS Lett. 1996, 399, 3, page 333-8) or myelin basic protein arewell described in the literature (e.g. Campos-González, R. and Glenney,Jr., J. R. 1992 J. Biol. Chem. 267, Page 14535).

For the identification of kinase inhibitors various assay systems areavailable (see for example Walters et al., Nature Drug Discovery 2003,2; page 259-266). For example, in scintillation proximity assays (e.g.Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) orflashplate assays the radioactive phosphorylation of a protein orpeptide as substrate with γATP can be measured. In the presence of aninhibitory compound no signal or a decreased radioactive signal isdetectable. Furthermore homogeneous time-resolved fluorescence resonanceenergy transfer (HTR-FRET), and fluorescence polarization (FP)technologies are useful for assay methods (for example Sills et al., J.of Biomolecular Screening, 2002, 191-214).

Other non-radioactive ELISA based assay methods use specificphospho-antibodies (AB). The phospho-AB binds only the phosphorylatedsubstrate. This binding is detectable with a secondary peroxidaseconjugated antibody, measured for example by chemiluminescence

The present invention provides compounds generally described as oxamidederivatives, including both aryl and/or heteroaryl derivatives which arepreferably kinase inhibitors and more preferably inhibitors of theenzyme raf kinase. Since the enzyme is a downstream effector ofp21^(ras), the inhibitors are useful in pharmaceutical compositions forhuman or veterinary use where inhibition of the raf kinase pathway isindicated, e.g., in the treatment of tumors and/or cancerous cell growthmediated by raf kinase. In particular, the compounds are useful in thetreatment of human or animal solid cancers, e.g. murine cancer, sincethe progression of these cancers is dependent upon the ras proteinsignal transduction cascade and therefore susceptible to treatment byinterruption of the cascade, i.e., by inhibiting raf kinase.Accordingly, the compound of Formula I or a pharmaceutically acceptablesalt thereof is administered for the treatment of diseases mediated bythe raf kinase pathway especially cancers, including solid cancers, suchas, for example, carcinomas (e.g., of the lungs, pancreas, thyroid,bladder or colon), myeloid disorders (e.g., myeloid leukemia) oradenomas (e.g., villous colon adenoma), pathological angiogenesis andmetastatic cell migration. Furthermore the compounds are useful in thetreatment of complement activation dependent chronic inflammation(Niculescu et al. (2002) Immunol. Res., 24:191-199) and HIV-1 (humanimmunodeficiency virus type1) induced immunodeficiency (Popik et al.(1998) J Virol, 72: 6406-6413) and infection disease, Influenza A virus(Pleschka, S. et al. (2001), Nat. Cell. Biol, 3(3):301-5) andHelicobacter pylori infection (Wessler, S. et al. (2002), FASEB J.,16(3): 417-9).

Therefore, subject of the present invention are oxamide derivatives offormula IA-D-B  (I)wherein

-   D is a bivalent oxamide moiety which is directly bonded to A and B,    preferably to one bonding partner via the N-nitrogen atom and to the    other bonding partner via the N′-nitrogen atom, wherein the    N-nitrogen atom and/or the N′-nitrogen atom is unsubstituted or    substituted with one or more substituents, wherein said substituents    are preferably selected from the group consisting of alkyl,    alkylene, haloalkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkylene,    heterocyclyl, aryl, aralkyl, heteroaryl, hydroxy, alkoxy,    haloalkoxy, aralkoxy, aryloxy, mercapto, alkylsulfanyl,    haloalkylsulfanyl, arylsulfanyl, heteroarylsulfanyl, alkylsulfenyl,    haloalkylsulfenyl, arylsulfenyl, heteroarylsulfenyl, alkylsulfonyl,    haloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxy, cyano,    cyanoalkyl, aminosulfonyl, acyl, acyloxy, carbamoyl, aroyl,    heteroaryl, heteroaroyloxy, unsubstituted amino groups and    substituted amino groups, and wherein one or both carbonyl groups of    said oxamide moiety can be derivatized, preferably to a C═S, C═NR⁵,    C═C(R⁵)—NO₂, C═C(R⁵)—CN or C═C(CN)₂ group-   A is a substituted moiety of up to 40 carbon atoms of the formula:    -L-(M-L′)_(α), where L is a 5, 6 or 7 membered cyclic structure,    preferably selected from the group consisting of aryl, heteroaryl,    arylene and heteroarylene, bound directly to D, L′ comprises an    optionally substituted cyclic moiety having at least 5 members,    preferably selected from the group consisting of aryl, heteroaryl,    aralkyl, cycloalkyl and heterocyclyl, M is a bond or a bridging    group having at least one atom, α is an integer of from 1-4; and    each cyclic structure of L and L′ contains 0-4 members of the group    consisting of nitrogen, oxygen and sulfur, wherein L′ is preferably    substituted by at least one substituent selected from the group    consisting of —SO_(β)R_(x), —C(O)R_(x) and —C(NR_(y))R_(z)-   B is a substituted or unsubstituted, up to tricyclic aryl or    heteroaryl moiety of up to 30 carbon atoms, preferably of up to 20    carbon atoms, comprising at least one 5-, 6-, or 7-membered cyclic    structure, preferably a 5- or 6-membered cyclic structure, bound    directly to D containing 0-4 members of the group consisting of    nitrogen, oxygen and sulfur, wherein said cyclic structure directly    bound to D is preferably selected from the group consisting of aryl,    heteroaryl and heterocyclyl,-   R_(y) is hydrogen or a carbon based moiety of up to 24 carbon atoms    optionally containing heteroatoms selected from N, S and O and    optionally halosubstituted, up to per halo,-   R_(z) is hydrogen or a carbon based moiety of up to 30 carbon atoms    optionally containing heteroatoms selected from N, S and O and    optionally substituted by halogen, hydroxy and carbon based    substituents of up to 24 carbon atoms, which optionally contain    heteroatoms selected from N, S and O and are optionally substituted    by halogen;-   R_(x) is R_(z) or NR_(a)R_(b), where R_(a) and R_(b) are    -   a) independently hydrogen, a carbon based moiety of up to 30        carbon atoms optionally containing heteroatoms selected from N,        S and O and optionally substituted by halogen, hydroxy and        carbon based substituents of up to 24 carbon atoms, which        optionally contain heteroatoms, selected from N, S and O, and        are optionally substituted by halogen, or        -   —OSi(R_(f))₃ where R_(f) is hydrogen or a carbon based            moiety of up to 24 carbon atoms optionally containing            heteroatoms selected from N, S and O and optionally            substituted by halogen, hydroxy and carbon based            substituents of up to 24 carbon atoms, which optionally            contain heteroatoms selected from N, S and O, and are            optionally substituted by halogen; or    -   b) R_(a) and R_(b) together from a 5-7 member heterocyclic        structure of 1-3 heteroatoms selected from N, S and O, or a        substituted 5-7 member heterocyclic structure of 1-3 heteroatoms        selected from N, S and O substituted by halogen, hydroxy or        carbon based substituents of up to 24 carbon atoms, which        optionally contain heteroatoms selected from N, S and O and are        optionally substituted by halogen; or        -   one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene            group or a substituted C₁-C₅ divalent alkylene group bound            to the moiety L to form a cyclic structure with at least 5            members, wherein the substituents of the substituted C₁-C₅            divalent alkylene group are selected from the group            consisting of halogen, hydroxy, and carbon based            substituents of up to 24 carbon atoms, which optionally            contain heteroatoms selected from N, S and O and are            optionally substituted by halogen; where B is substituted, L            is substituted or L′ is additionally substituted, the            substituents are selected from the group consisting of            halogen, up to per-halo and Wγ, where γ is 0-3;        -   wherein each W is independently selected from the group            consisting of —CN, —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵,            —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, -Q-Ar,            and carbon based moieties of up to 24 carbon atoms,            optionally containing heteroatoms selected from N, S and O            and optionally substituted by one or more substituents            independently selected from the group consisting of —CN,            —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵,            —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵ and halogen up to            per-halo; with each R⁵ independently selected from H or a            carbon based moiety of up to 24 carbon atoms, optionally            containing heteroatoms selected from N, S and O and            optionally substituted by halogen;        -   wherein Q is —O—, —S—, —N(R⁵)—, —(CH₂)_(β), —C(O)—,            —CH(OH)—, —(CH₂)_(β)—O—, —(CH₂)_(β)—S—, —(CH₂)_(β)N(R⁵)—,            —O(CH₂)₆₂ —CHHal-, —CHal₂-, —S—(CH₂)— and —N(R⁵)(CH₂)_(β)—            where β=1-3, and Hal is halogen; and        -   Ar is a 5- or 6-member aromatic structure containing 0-2            members selected from the group consisting of nitrogen,            oxygen and sulfur, which is optionally substituted by            halogen, up to per-halo, and optionally substituted by            Z_(δ1) wherein δ1 is 0 to 3 and each Z is independently            selected from the group consisting —CN, —CO₂R⁵, —C(O)NR⁵R⁵,            —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,            —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, and a carbon based moiety of up to            24 carbon atoms, optionally containing heteroatoms selected            from N, S and O and optionally substituted by one or more            substituents selected from the group consisting of —CN,            —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵,            —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, and with R⁵ as            defined above,        -   and the pharmaceutically acceptable derivatives, solvates,            salts and stereoisomers thereof, including mixtures thereof            in all ratios, and more preferred the salts and/or solvates            thereof, and especially preferred the physiologically            acceptable salts and/or solvates thereof.

More preferred, in the compound of formula I,

-   R_(y) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₂₋₁₀ alkenyl, C₁₋₁₀    alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected    from N, S and O, C₇₋₂₄ aralkyl, C₇₋₂₄ alkaryl, substituted C₁₋₁₀    alkyl, substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl having    0-3 heteroatoms selected from N, S and O, substituted C₆-C₁₄ aryl,    substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S    and O, substituted C₇₋₂₄ alkaryl or substituted C₇₋₂₄ aralkyl, where    Ry is a substituted group, it is substituted by halogen up to per    halo,-   R_(z) is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl    having 0-3 heteroatoms, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl, C₆₋₁₂ aryl,    C₃-C₁₂ hetaryl having 1-3 heteroatoms selected form S, N and O,    C₇₋₂₄ alkaryl, C₇₋₂₄ aralkyl, substituted C₃-C₁₀ cycloalkyl having    0-3 heteroatoms selected from S, N and O, substituted C₃₋₁₂ hetaryl    having 1-3 heteroatoms selected from S, N and O, substituted C₇₋₂₄    alkaryl or substituted C₇-C₂₄ aralkyl where R_(z) is a substituted    group, it is substituted by halogen up to per halo, hydroxy, C₁₋₁₀    alkyl, C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected from N, S    and O, substituted C₃-C₁₂ hetaryl having 1-3 heteroatoms selected    from N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl, C₁₋₆ halo substituted    alkyl up to per halo alkyl, C₆-C₁₂ halo substituted aryl up to per    halo aryl, C₃-C₁₂ halo substituted cycloalkyl up to per halo    cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo    substituted C₃-C₁₂ hetaryl up to per halo, hetaryl having 1-3    heteroatoms selected from O, N and S, halo substituted C₇-C₂₄    aralkyl up to per halo aralkyl, halo substituted C₇-C₂₄ alkaryl up    to per halo alkaryl, and —C(O)R_(g),-   R_(a) and R_(b) are:    -   a) independently hydrogen, a carbon based moiety selected from        the group consisting of C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₃₋₁₀        cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀ alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂        hetaryl having 1-3 heteroatoms selected from O, N and S, C₃₋₁₂        cycloalkyl having 0-3 heteroatoms selected from N, S and O,        C₇₋₂₄ aralkyl, C₇-C₂₄ alkaryl, substituted C₁₋₁₀ alkyl,        substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀ cycloalkyl, having        0-3 heteroatoms selected from N, S and O, substituted C₆₋₁₂        aryl, substituted C₃₋₁₂ hetaryl having 1-3 heteroatoms selected        from N, S and O, substituted C₇₋₂₄ aralkyl, substituted C₇₋₂₄        alkaryl; where R_(a) and R_(b) are a substituted group, they are        substituted by halogen up to per halo, hydroxy, C₁₋₁₀ alkyl,        C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected from O, S and        N, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from N, S and        O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl, C₁₋₆ halo substituted alkyl up to        per halo alkyl, C₆-C₁₂ halo substituted aryl up to per halo        aryl, C₃-C₁₂ halo substituted cycloalkyl having 0-3 heteroatoms        selected from N, S and O, up to per halo cycloalkyl, halo        substituted C₃-C₁₂ hetaryl up to per halo heteraryl, halo        substituted C₇-C₂₄ aralkyl up to per halo aralkyl, halo        substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and        —C(O)R_(g); or        -   —OSi(R_(f))₃ where R_(f) is hydrogen, C₁-C₁₀ alkyl, C₁-C₁₀            alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₀ alkenoyl, C₆₋₁₂            aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms selected from O,            N and S, C₃₋₁₂ cycloalkyl having 0-3 heteroatoms selected            from N, S and O, C₇₋₂₄ aralkyl, C₇-C₂₄ alkaryl, substituted            C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkoxy, substituted C₃₋₁₀            cycloalkyl, having 0-3 heteroatoms selected from N, S and O,            substituted C₆₋₁₂ aryl, substituted C₃₋₁₂ hetaryl having 1-3            heteroatoms selected from N, S and O, substituted C₇₋₂₄            aralkyl, substituted C₇₋₂₄ alkaryl, or    -   b) R_(a) and R_(b) together form a 5-7 member heterocyclic        structure of 1-3 heteroatoms selected from N, S and O, or a        substituted 5-7 member heterocyclic structure of 1-3 heteroatoms        selected from N, S and O with substituents selected from the        group consisting of halogen up to per halo, hydroxy, C₁-C₁₀        alkyl, C₁-C₁₀ alkoxy, C₃₋₁₀ cycloalkyl, C₂₋₁₀ alkenyl, C₁₋₁₀        alkenoyl, C₆₋₁₂ aryl, C₃₋₁₂ hetaryl having 1-3 heteroatoms        selected from O, N and S, C₃₋₁₂ cycloalkyl having 0-3        heteroatoms selected from N, S and O, C₇₋₂₄ aralkyl, C₇-C₂₄        alkaryl, substituted C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkoxy,        substituted C₃₋₁₀ cycloalkyl, having 0-3 heteroatoms selected        from N, S and O, substituted C₆₋₁₂ aryl, substituted C₃₋₁₂        hetaryl having 1-3 heteroatoms selected from N, S and O,        substituted C₇₋₂₄ aralkyl, substituted C₇₋₂₄ alkaryl, where        R_(a) and R_(b) are a substituted group, they are substituted by        halogen up to per halo, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl        having 0-3 heteroatoms selected from O, S and N, C₃₋₁₂ hetaryl        having 1-3 heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy,        C₆₋₁₂ aryl, C₁₋₆ halo substituted alkyl up to per halo alkyl,        C₆-C₁₂ halo substituted aryl up to per halo aryl, C₃-C₁₂ halo        substituted cycloalkyl having 0-3 heteroatoms selected from N, S        and O, up to per halo cycloalkyl, halo substituted C₃-C₁₂        hetaryl up to per halo heteraryl, halo substituted C₇-C₂₄        aralkyl up to per halo aralkyl, halo substituted C₇-C₂₄ alkaryl        up to per halo alkaryl, and —C(O)R_(g), or    -   c) one of R_(a) or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene        group or a substituted C₁-C₅ divalent alkylene group bound to        the moiety L to form a cyclic structure with at least 5 members,        wherein the substituents of the substituted C₁-C₅ divalent        alkylene group are selected from the group consisting of        halogen, hydroxy, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl having 0-3        heteroatoms selected from, S, O and N, C₃₋₁₂ hetaryl having 1-3        heteroatoms selected from N, S and O, C₁₋₁₀ alkoxy, C₆₋₁₂ aryl,        C₇-C₂₄ alkaryl, C₇-C₂₄ aralkyl, C₁₋₆ halo substituted alkyl up        to per halo alkyl, C₆-C₁₂ halo substituted aryl up to per halo        aryl, C₃-C₁₂ halo substituted cycloalkyl having 0-3 heteroatoms        selected from N, S and O, up to per halo cycloalkyl, halo        substituted C₃-C₁₂ hetaryl up to per halo heteraryl, halo        substituted C₇-C₂₄ aralkyl up to per halo aralkyl, halo        substituted C₇-C₂₄ alkaryl up to per halo alkaryl, and        —C(O)R_(g),        -   where R_(g) is C₁₋₁₀ alkyl; —CN, —CO₂R_(d), —OR_(d),            —SR_(d), —SO₂R_(d), —SO₃H, —NO₂, —C(O)R_(e), —NR_(d)R_(e),            —NR_(d)C(O)OR_(e) and —NR_(d)(CO)R_(e) and R_(d) and R_(e)            are independently selected from the group consisting of            hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, C₃₋₁₀ cycloalkyl having            0-3 heteroatoms selected from O, N and S, C₆₋₁₂ aryl, C₃-C₁₂            hetaryl with 1-3 heteroatoms selected from O, N and S,            C₇-C₂₄ aralkyl, C₇-C₂₄ alkaryl, up to per halo substituted            C₁-C₁₀ alkyl, up to per halo substituted C₃-C₁₀ cycloalkyl            having 0-3 heteroatoms selected from O, N and S, up to per            halo substituted C₆-C₁₄ aryl, up to per halo substituted            C₃-C₁₂ hetaryl having 1-3 heteroatoms selected from O, N and            S, halo substituted C₇-C₂₄ alkaryl up to per halo alkaryl,            and up to per halo substituted C₇-C₂₄ aralkyl,-   W is independently selected from the group consisting —CN, —CO₂R⁵,    —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,    —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₂-C₁₀    alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3 heteroatoms    selected from O, S and N, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl, C₇-C₂₄    aralkyl, C₃-C₁₂ heteroaryl having 1-3 heteroatoms selected form O, N    and S, C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected from O,    N and S, substituted C₁-C₁₀ alkyl, substituted C₁-C₁₀ alkoxy,    substituted C₂-C₁₀ alkenyl, substituted C₁-C₁₀ alkenoyl, substituted    C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected from O, N and S,    substituted C₆-C₁₂ aryl, substituted C₃-C₁₂ hetaryl having 1-3    heteroatoms selected from O, N and S, substituted C₇-C₂₄ aralkyl,    substituted C₇-C₂₄ alkaryl, substituted C₄-C₂₃ alkheteroaryl having    1-3 heteroatoms selected from O, N and S, and -Q-Ar;-   R⁵ is independently selected from H. C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy,    C₂-C₁₀ alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3    heteroatoms selected from O, S and N, C₆-C₁₄ aryl, C₃-C₁₃ hetaryl    having 1-3 heteroatoms selected from O, N and S, C₇-C₁₄ alkaryl,    C₇-C₂₄ aralkyl, C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected    from O, N and S, up to per-halosubstituted C₁-C₁₀ alkyl, up to    per-halosubstituted C₃-C₁₀ cycloalkyl having 0-3 heteroatoms    selected from O, N and S, up to per-halosubstituted C₆-C₁₄ aryl, up    to per-halosubstituted C₃-C₁₃ hetaryl having 1-3 heteroatoms    selected from O, N and S, up to per-halosubstituted C₇-C₂₄ aralkyl,    up to per-halosubstituted C₇-C₂₄ alkaryl, and up to    per-halosubstituted C₄-C₂₃ alkheteroaryl; and each-   Z is independently selected from the group consisting —CN, —CO₂R⁵,    —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,    —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, C₂-C₁₀    alkenyl, C₁-C₁₀ alkenoyl, C₃-C₁₀ cycloalkyl having 0-3 heteroatoms    selected from O, S and N, C₆-C₁₄ aryl, C₇-C₂₄ alkaryl, C₇-C₂₄    aralkyl, C₃-C₁₂ heteroaryl having 1-3 heteroatoms selected from O, N    and S, C₄-C₂₃ alkheteroaryl having 1-3 heteroatoms selected from O,    N and S, substituted C₁-C₁₀ alkyl, substituted C1-C10 alkoxy,    substituted C₂-C₁₀ alkenyl, substituted C₁-C₁₀ alkenoyl, substituted    C₃-C₁₀ cycloalkyl having 0-3 heteroatoms selected from O, N and S,    substituted C₆-C₁₂ aryl, substituted C₃-C₁₂ hetaryl having 1-3    heteroatoms selected from O, N and S; wherein if Z is a substituted    group, the one or more substituents are selected from the group    consisting of —CN, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵,    —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵.

According to the invention, each M independently from one anotherrepresents a bond or is a bridging group, selected from the groupconsisting of (CR⁵R⁵)_(h), or (CHR⁵)_(h)-Q-(CHR⁵)_(i), wherein

-   Q is selected from a group consisting of O, S, N—R⁵, (CHal₂)_(j),    (O—CHR⁵)_(j), (CHR⁵—O)_(j), CR⁵═CR⁵, (O—CHR⁵CHR⁵)_(j),    (CHR⁵CHR⁵—O)_(j), C═O, C═S, C═NR⁵, CH(OR⁵), C(OR⁵)(OR⁵), C(═O)O,    OC(═O), OC(═O)O, C(═O)N(R⁵), N(R⁵)C(═O), OC(═O)N(R⁵), N(R⁵)C(═O)O,    CH═N—O, CH═N—NR⁵, OC(O)NR⁵, NR⁵C(O)O, S═O, SO₂, SO₂NR⁵ and NR⁵SO₂,    wherein-   R⁵ is in each case independently selected from the meanings given    above, preferably from hydrogen, halogen, alkyl, aryl, aralkyl,-   h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6,    preferably 0, 1, 2, or 3, and-   j is 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2 or 3.

More preferred, each M independently from one another represents a bondor is a bridging group, selected from the group consisting of —O—, —S—,—N(R⁵)—, —(CH₂)_(β)—, —C(O)—, —CH(OH)—, —(CH₂)_(β)O—, —(CH₂)_(β)S—,—(CH₂)_(β)N(R⁵)—, —O(CH₂)_(β), —CHHal-, —CHal₂-, —S—(CH₂)_(β)— and—N(R⁵)(CH₂)_(β), where β is 1 to 6 and especially preferred 1 to 3, Halis halogen and R⁵ is as defined above. More preferred, the group B ofFormula I is a substituted or unsubstituted six member aryl moiety orsix member hetaryl moiety, said hetaryl moiety having 1 to 4 membersselected from the group of hetaryl atoms consisting of nitrogen, oxygenand sulfur with the balance of the hetaryl moiety being carbon.

Even more preferred, the group B of Formula I is

-   a) an unsubstituted phenyl group, an unsubstituted pyridyl group, an    unsubstituted pyrimidinyl, a phenyl group substituted by a    substituent selected from the group consisting of halogen and Wγ    wherein W and γ are as defined in claim 1, a pyrimidinyl group    substituted by a substituent selected from the group constituting of    halogen and Wγ, whereas W and γ are as defined above, or a    substituted pyridyl group, substituted by a substituent selected    from the group consisting of halogen and Wγ wherein W and γ are as    defined above; or a substituted phenyl group, a substituted    pyrimidinyl group, or substituted pyridyl group substituted 1 to 3    times by 1 or more substituents selected from the group consisting    of —CN, halogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl alkoxy, —OH, up to per    halo substituted C₁-C₁₀ alkyl, up to per halo substituted C₁-C₁₀    alkoxy or phenyl substituted by halogen up to per halo; or-   b) a substituted phenyl group, a substituted pyrimidinyl group, or    substituted pyridyl group substituted 1 to 3 times by 1 or more    substituents selected from the group consisting of CN, halogen,    alkyl, especially C₁-C₄ alkyl, alkoxy, especially C₁-C₄ alkoxy, OH,    up to per halo substituted alkyl, especially up to per halo    substituted C₁-C₄ alkyl, up to per halo substituted alkoxy,    especially up to per halo substituted C₁-C₄ alkoxy or phenyl    substituted by halogen up to per halo.

In the formula I, the group L which is directly bound to D is preferablya substituted or unsubstituted 6 member aryl moiety or a substituted orunsubstituted 6 member hetaryl moiety, wherein said hetaryl moiety has 1to 4 members selected from the group of heteroatoms consisting ofnitrogen, oxygen and sulfur with the balance of said hetaryl moietybeing carbon, wherein the one or more substituents are selected from thegroup consisting of halogen and Wγ wherein W and γ are as defined above.

More preferred, the group L is a substituted phenyl, unsubstitutedphenyl, substituted pyrimidinyl, unsubstituted pyrimidinyl, substitutedpyridyl or unsubstituted pyridyl group.

In the formula I, the group L′ preferably comprises a 5 to 6 memberedaryl moiety or hetaryl moiety, wherein said heteraryl moiety comprises 1to 4 members selected from the group of heteroatoms consisting ofnitrogen, oxygen and sulfur.

More preferred, the group L′ is phenyl, pyridinyl or pyrimidinyl.

Oxamides are also known as oxalic amides or oxalic acid diamides. Thus,an oxamide moiety according to the invention is a bivalent radicalwherein one of the nitrogen atoms of the oxamide moiety is bondeddirectly to A and the other nitrogen atom of the oxamide moiety isbonded directly to B. The hydrogen atoms of one or both nitrogen atomsof the oxamide moiety can be substituted by suitable substituents,preferably selected from the group consisting of alkyl, alkylene,haloalkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkylene, heterocyclyl, aryl,aralkyl, heteroaryl, carboxy, cyanoalkyl, acyl and heteroaryl.Preferably, both nitrogen atoms of the oxamide moiety are unsubstituted.In this respect, one or both of the nitrogen atoms of the oxamide moietycan, independently from one another, optionally be deprotonated,protonated and/or quarternized. The resulting ions or salts are alsosubject of the present invention.

Accordingly, preferred compounds of formula I are of formula Ia

wherein A and B are as defined above/below, each Y is independentlyselected from O, S, NR⁵, C(R⁵)—NO₂, C(R⁵)—CN and C═C(CN)₂, and whereinR⁶ and R⁷ are independently selected from the group consisting of H,alkyl, alkylene, haloalkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkylene,heterocyclyl, aryl, aralkyl, heteroaryl, carboxy, cyanoalkyl, acyl andheteroaryl, and the salts or solvates thereof. More preferred arecompounds of formula Ia, wherein one or both of the residues Y are Oand/or wherein one or both of the residues R⁶ and R⁷ are H. Furtherpreferred compounds of formula I are the pharmaceutically acceptablederivatives, solvates, salts and stereoisomers of formula Ia, includingmixtures thereof in all ratios, and more preferred the salts and/orsolvates thereof, and especially preferred the physiologicallyacceptable salts and/or solvates thereof.

Accordingly, one aspect of the instant invention relates to compounds offormula Ib,

wherein A and B are as defined above/below, and the pharmaceuticallyacceptable derivatives, solvates, salts and stereoisomers thereof,including mixtures thereof in all ratios, and more preferred the saltsand/or solvates thereof, and especially preferred the physiologicallyacceptable salts and/or solvates thereof.

Preferably, A or B is substituted by one or more substituents asdescribed above/below. More preferably, A and B each are substituted byone or more substituents as described above/below. Even more preferably,A is substituted by two or more substituents as described above/below.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “alkyl” preferably refers to a straight orbranched chain hydrocarbon having from one to twelve carbon atoms,optionally substituted with substituents selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen, or C₁-C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkyl” as used herein include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, n-pentyl, isopentyl, and the like.

As used herein, the term “C₁-C₆ alkyl” preferably refers to an alkylgroup as defined above containing at least 1, and at most 6, carbonatoms. Examples of branched or straight chained “C₁-C₆ alkyl” groupsuseful in the present invention include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl andisopentyl.

As used herein, the term “alkylene” preferably refers to a straight orbranched chain divalent hydrocarbon radical having from one to tencarbon atoms, optionally substituted with substituents selected from thegroup which includes lower alkyl, lower alkoxy, lower alkylsulfanyl,lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl, optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene and the like.

As used herein, the term “C₁-C₆ alkylene” preferably refers to analkylene group, as defined above, which contains at least 1, and at most6, carbon atoms respectively. Examples of “C₁-C₆ alkylene” groups usefulin the present invention include, but are not limited to, methylene,ethylene and n-propylene.

As used herein, the term “halogen” or “hal” preferably refers tofluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

As used herein, the term “C₁-C₆ haloalkyl” preferably refers to an alkylgroup as defined above containing at least 1, and at most 6, carbonatoms substituted with at least one halogen, halogen being as definedherein. Examples of branched or straight chained “C₁-C₆ haloalkyl”groups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substitutedindependently with one or more halogens, e.g., fluoro, chloro, bromo andiodo.

As used herein, the term “C₃-C₇ cycloalkyl” preferably refers to anon-aromatic cyclic hydrocarbon ring having from three to seven carbonatoms and which optionally includes a C₁-C₆ alkyl linker through whichit may be attached. The C₁-C₆ alkyl group is as defined above. Exemplary“C₃-C₇ cycloalkyl” groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term“cycloalkyl”, as used herein preferably also includes saturatedheterocyclic groups, which are preferably selected from thecycloalkyl-groups as defined above, wherein one or two carbon atoms arereplaced by hetero atoms, selected from the group consisting of O, N andS.

As used herein, the term “C₃-C₇ cycloalkylene” preferably refers to anon-aromatic alicyclic divalent hydrocarbon radical having from three toseven carbon atoms, optionally substituted with substituents selectedfrom the group which includes lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”preferably refers to a three to twelve-membered heterocyclic ring havingone or more degrees of unsaturation containing one or more heteroatomicsubstitutions selected from S, SO, SO₂, O or N, optionally substitutedwith substituents selected from the group consisting of C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆haloalkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen, or C₁-C₆ perfluoroalkyl,multiple degrees of substitution being allowed. Such a ring may beoptionally fused to one or more other “heterocyclic” ring(s) orcycloalkyl ring(s). Examples of “heterocyclic” moieties include, but arenot limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane,pyrrolidine, piperidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” preferably refers to a threeto twelve-membered heterocyclic ring diradical having one or moredegrees of unsaturation containing one or more heteroatoms selected fromS, SO, SO₂, O or N, optionally substituted with substituents selectedfrom the group which includes lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Such a ring may be optionally fused to oneor more benzene rings or to one or more of another “heterocyclic” ringsor cycloalkyl rings. Examples of “heterocyclylene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl,pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl,piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl,morpholine-2,4-diyl, and the like.

As used herein, the term “aryl” preferably refers to an optionallysubstituted benzene ring or to an optionally substituted benzene ringsystem fused to one or more optionally substituted benzene rings toform, for example, anthracene, phenanthrene, or napthalene ring systems.Exemplary optional substituents include C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁-C₅perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “aryl” groups include, but are not limited toPhenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substitutedderivatives thereof.

As used herein, the term “arylene” preferably refers to a benzene ringdiradical or to a benzene ring system diradical fused to one or moreoptionally substituted benzene rings, optionally substituted withsubstituents selected from the group which includes lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl and aryl, multiple degrees of substitutionbeing allowed. Examples of “arylene” include, but are not limited tobenzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and thelike.

As used herein, the term “aralkyl” preferably refers to an aryl orheteroaryl group, as defined herein, attached through a C₁-C₆ alkyllinker, wherein C₁-C₆ alkyl is as defined herein. Examples of “aralkyl”include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl,3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl and 2-imidazolylethyl.

As used herein, the term “heteroaryl” preferably refers to a monocyclicfive to seven-membered aromatic ring, or to a fused bicyclic aromaticring system comprising two of such monocyclic five to seven-memberedaromatic rings. These hetroaryl rings contain one or more nitrogen,sulfur and/or oxygen heteroatoms, where N-Oxides and sulfur Oxides anddioxides are permissible heteroatom substitutions and may be optionallysubstituted with up to three members selected from a group consisting ofC₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆haloalkylsulfanyl, C₁-C₆ alkylsulfenyl, C₁-C₆ alkylsulfonyl, oxo,hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C₁-C₆perfluoroalkyl, heteroaryl or aryl, multiple degrees of substitutionbeing allowed. Examples of “heteroaryl” groups used herein includefuranyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl,thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl,quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl,indazolyl, and substituted versions thereof. As used herein, the term“heteroarylene” preferably refers to a five- to seven-membered aromaticring diradical, or to a polycyclic heterocyclic aromatic ring diradical,containing one or more nitrogen, oxygen, or sulfur heteroatoms, whereN-Oxides and sulfur monoxides and sulfur dioxides are permissibleheteroaromatic substitutions, optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. For polycyclic aromatic ring system diradicals, one ormore of the rings may contain one or more heteroatoms. Examples of“heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl,1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike. As used herein, the term “alkoxy” preferably refers to the groupR_(a)O—, where R_(a) is alkyl as defined above and the term “C₁-C₆alkoxy” preferably refers to an alkoxy group as defined herein whereinthe alkyl moiety contains at least 1 and at most 6 carbon atoms.Exemplary C₁-C₆ alkoxy groups useful in the present invention include,but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxyand t-butoxy.

As used herein, the term “haloalkoxy” preferably refers to the groupR_(a)O—, where R_(a) is haloalkyl as defined above and the term “C₁-C₆haloalkoxy” preferably refers to an haloalkoxy group as defined hereinwherein the haloalkyl moiety contains at least 1 and at most 6 carbonatoms. Exemplary C₁-C₆ haloalkoxy groups useful in the present inventioninclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy and t-butoxy substituted with one or more halo groups, forinstance trifluoromethoxy.

As used herein the term “aralkoxy” preferably refers to the groupR_(C)R_(B)O—, where R_(B) is alkylene and R_(C) is aryl as definedabove.

As used herein the term “aryloxy” preferably refers to the groupR_(C)O—, where R_(C) is aryl as defined above.

As used herein, the term “alkylsulfanyl” preferably refers to the groupR_(A)S—, where R_(A) is alkyl as defined above and the term “C₁-C₆alkylsulfanyl” preferably refers to an alkylsulfanyl group as definedherein wherein the alkyl moiety contains at least 1 and at most 6 carbonatoms.

As used herein, the term “haloalkylsulfanyl” preferably refers to thegroup R_(D)S—, where R_(D) is haloalkyl as defined above and the term“C₁-C₆ haloalkylsulfanyl” preferably refers to a haloalkylsulfanyl groupas defined herein wherein the alkyl moiety contains at least 2 and atmost 6 carbon atoms.

As used herein, the term “alkylsulfenyl” preferably refers to the groupR_(A)S(O)—, where R_(A) is alkyl as defined above and the term “C₁-C₆alkylsulfenyl” preferably refers to an alkylsulfenyl group as definedherein wherein the alkyl moiety contains at least 1 and at most 6 carbonatoms.

As used herein, the term “alkylsulfonyl” preferably refers to the groupR_(A)SO₂—, where R_(A) is alkyl as defined above and the term “C₁-C₆alkylsulfonyl” preferably refers to an alkylsulfonyl group as definedherein wherein the alkyl moiety contains at least 1 and at most 6 carbonatoms.

As used herein, the term “oxo” preferably refers to the group ═O.

As used herein, the term “mercapto” preferably refers to the group —SH.

As used herein, the term “carboxy” preferably refers to the group —COOH.

As used herein, the term “cyano” preferably refers to the group —CN.

As used herein, the term “cyanoalkyl” preferably refers to the group—R_(B)CN, wherein R_(B) is alkylene as defined above. Exemplary“cyanoalkyl” groups useful in the present invention include, but are notlimited to, cyanomethyl, cyanoethyl and cyanoisopropyl.

As used herein, the term “aminosulfonyl” preferably refers to the group—SO₂NH₂.

As used herein, the term “carbamoyl” preferably refers to the group—C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or—SO₂—.

As used herein, the term “acyl” preferably refers to the groupR_(F)C(O)—, where R_(F) is alkyl, cycloalkyl or heterocyclyl as definedherein.

As used herein, the term “aroyl” preferably refers to the groupR_(C)C(O)—, where R_(C) is aryl as defined herein.

As used herein, the term “heteroaroyl” preferably refers to the groupR_(E)C(O)—, where R_(E) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” preferably refers to the groupR_(A)OC(O)—, where R_(A) is alkyl as defined herein.

As used herein, the term “acyloxy” preferably refers to the groupR_(F)C(O)O—, where R_(F) is alkyl, cycloalkyl, or heterocyclyl asdefined herein.

As used herein, the term “aroyloxy” preferably refers to the groupR_(C)C(O)O—, where R_(C) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” preferably refers to the groupR_(E)C(O)O—, where R_(E) is heteroaryl as defined herein.

As used herein, the term “carbonyl” or “carbonyl moiety” preferablyrefers to the group C═O.

As used herein, the term “thiocarbonyl” or “thiocarbonyl moiety”preferably refers to the group C═S.

As used herein, the term “amino”, “amino group” or “amino moiety”preferably refers to the group NR_(G)R_(G′), wherein R_(G) and R_(G′),are preferably selected, independently from one another, from the groupconsisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl,alkylenecycloalkyl, cyanoalkyl, aryl, aralkyl, heteroaryl, acyl andaroyl. If both R_(G) and R_(G′) are hydrogen, NR_(G)R_(G′) is alsoreferred to as “unsubstituted amino moiety” or “unsubstituted aminogroup”. If R_(G) and/or R_(G′) are other than hydrogen, NR_(G)R_(G′) isalso referred to as “substituted amino moiety” or “substituted aminogroup”.

As used herein, the term “imino” or “imino moiety” preferably refers tothe group C═NR_(G), wherein R_(G) is preferably selected from the groupconsisting of hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl,alkylenecycloalkyl, cyanoalkyl, aryl, aralkyl, heteroaryl, acyl andaroyl. If R_(G) is hydrogen, C═NR_(G) is also referred to as“unsubstituted imino moiety”. If R_(G) is a residue other than hydrogen,C═NR_(G) is also referred to as “substituted imino moiety”.

As used herein, the term “ethene-1,1-diyl moiety” preferably refers tothe group C═CR_(K)R_(L), wherein R_(K) and R_(L) are preferablyselected, independently from one another, from the group consisting ofhydrogen, halogen, alkyl, haloalkyl, alkenyl, cycloalkyl, nitro,alkylenecycloalkyl, cyanoalkyl, aryl, aralkyl, heteroaryl, acyl andaroyl. If both hydrogen R_(K) and R_(L) are hydrogen, C═CR_(K)R_(L) isalso referred to as “unsubstituted ethene-1,1-diyl moiety”. If one ofR_(K) and R_(L) or both are a residue other than hydrogen, C═CR_(K)R_(L)is also referred to as “substituted ethene-1,1-diyl moiety”.

As used herein, the terms “group”, “residue” and “radical” or “groups”,“residues” and “radicals” are usually used as synonyms, respectively, asit is common practice in the art.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s),which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative”preferably refers to any pharmaceutically acceptable derivative of acompound of the present invention, for example, an ester or an amide,which upon administration to a mammal is capable of providing (directlyor indirectly) a compound of the present invention or an activemetabolite thereof. Such derivatives are clear to those skilled in theart, without undue experimentation, and with reference to the teachingof Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” preferably refers to a complex ofvariable stoichiometry formed by a solute (in this invention, a compoundof formula I or formula II or a salt or physiologically functionalderivative thereof and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Examples of suitable solvents include, but are not limited to, water,methanol, ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term “substituted” preferably refers to substitutionwith the named substituent or substituents, multiple degrees ofsubstitution being allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two or morestereoisomers, which are usually enantiomers and/or diastereomers.Accordingly, the compounds of this invention include mixtures ofstereoisomers, especially mixtures of enantiomers, as well as purifiedstereoisomers, especially purified enantiomers, or stereoisomericallyenriched mixtures, especially enantiomerically enriched mixtures. Alsoincluded within the scope of the invention are the individual isomers ofthe compounds represented by formulae I and II above as well as anywholly or partially equilibrated mixtures thereof. The present inventionalso covers the individual isomers of the compounds represented by theformulas above as mixtures with isomers thereof in which one or morechiral Centers are inverted. Also, it is understood that all tautomersand mixtures of tautomers of the compounds of formulae (I) or (II) areincluded within the scope of the compounds of formulae (I) and (II) andpreferably the formulae and subformulae corresponding thereto.

Racemates obtained can be resolved into the isomers mechanically orchemically by methods known per se. Diastereomers are preferably formedfrom the racemic mixture by reaction with an optically active resolvingagent. Examples of suitable resolving agents are optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids, such asβ-camphorsulfonic acid. Also advantageous is enantiomer resolution withthe aid of a column filled with an optically active resolving agent (forexample dinitrobenzoylphenyl-glycine); an example of a suitable eluentis a hexane/isopropanol/acetonitrile mixture.

The diastereomer resolution can also be carried out by standardpurification processes, such as, for example, chromatography orfractional crystallization.

It is of course also possible to obtain optically active compounds ofthe formula I or II by the methods described above by using startingmaterials which are already optically active.

Unless indicated otherwise, it is to be understood that reference tocompounds of formula I preferably includes the reference to thecompounds of formula II. Unless indicated otherwise, it is to beunderstood that reference to the compounds of formula II preferablyincludes the reference to the sub formulae corresponding thereto, forexample the sub formulae II.1 to II.20 and preferably formulae IIa toIIh. It is also understood that the following embodiments, includinguses and compositions, although recited with respect to formula I arepreferably also applicable to formulae II, sub formulae II1 to II.20 andpreferably formulae IIa to IIh.

Especially preferred compounds according to the invention are compoundsof formula II

wherein

-   Ar¹, Ar² are selected independently from one another from aromatic    hydrocarbons containing 6 to 14 carbon atoms and ethylenical    unsaturated or aromatic heterocyclic residues containing 3 to 10    carbon atoms and one or two heteroatoms, independently selected from    N, O and S,-   R⁸, R⁹ and R¹⁰ are independently selected from a group consisting of    H, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal,    CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹²,    (CH₂)_(n)OR¹¹, (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹²,    (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹²,    (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³,    (CH₂)_(n)OC(O)R¹³, (CH₂)_(n)COR¹³⁻; (CH₂)_(n)SR¹¹, CH═N—OA,    CH₂CH═N—OA, (CH₂)_(n)NHOA, (CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹²,    (CH₂)_(n)NR¹¹COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³,    (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃, (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹²,    C(R¹³)HCOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹²,    (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹², CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹²,    CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³, (CH₂)_(n)N(COOR¹¹)COOR¹²,    (CH₂)_(n)N(CONH₂)COOR¹¹, (CH₂)_(n)N(CONH₂)CONH₂,    (CH₂)_(n)N(CH₂COOR¹¹)COOR¹², (CH₂)_(n)N(CH₂CONH₂)COOR¹¹,    (CH₂)_(n)N(CH₂CONH₂)CONH₂, (CH₂)_(n)CHR¹³COR¹¹,    (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹⁴, (CH₂)_(n)OCN and    (CH₂)_(n)NCO, wherein-   R¹¹, R¹² are independently selected from a group consisting of H, A,    (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or in NR¹¹R¹²,-   R¹¹ and R¹² form, together with the N-Atom they are bound to, a 5-,    6- or 7-membered heterocyclus which additionaly contains 1 or 2    hetero atoms, selected from N, O an S,-   R¹³, R¹⁴ are independently selected from a group consisting of H,    Hal, A, (CH₂)_(m)Ar⁴ and (CH₂)_(m)Het,-   A is selected from the group consisting of alkyl, alkenyl,    cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl,-   Ar³, Ar⁴ are independently from one another aromatic hydrocarbon    residues comprising 5 to 12 and preferably 5 to 10 carbon atoms    which are optionally substituted by one or more substituents,    selected from a group consisting of A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶,    COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵,    SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵,-   Het is a saturated, unsaturated or aromatic heterocyclic residue    which is optionally substituted by one ore more substituents,    selected from a group consisting of A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶,    COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵,    SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵,-   R¹⁵, R¹⁶ are independently selected from a group consisting of H, A,    and (CH₂)_(m)Ar⁶, wherein-   Ar⁶ is a 5- or 6-membered aromatic hydrocarbon which is optionally    substituted by one or more substituents selected from a group    consisting of methyl, ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN,    OH, NH₂ and CF₃,-   k, m and n are independently of one another 0, 1, 2, 3, 4, or 5,-   X represents a bond or is (CR¹¹R¹²)_(h), or    (CHR¹¹)_(h)-Q-(CHR¹²)_(j), wherein-   Q is selected from a group consisting of O, S, N—R¹⁵, (CHal₂)_(j),    (O—CHR¹⁸)_(j), (CHR¹⁸—O)_(j), CR¹⁸═CR¹⁹, (O—CHR¹⁸CHR¹⁹)_(j),    (CHR¹⁸CHR¹⁹—O)_(j), C═O, C═S, C═NR¹⁵, CH(OR¹⁵), C(OR¹⁵)(OR²⁰),    C(═O)O, OC(═O), OC(═O)O, C(═O)N(R¹⁵), N(R¹⁵)C(═O), OC(═O)N(R¹⁵),    N(R¹⁵)C(═O)O, CH═N—O, CH═N—NR¹⁵, S═O, SO₂, SO₂NR¹⁵ and NR¹⁵SO₂,    wherein-   R¹⁸, R¹⁹, R²⁰ are independently selected from the meanings given for    R⁸, R⁹ and R¹⁰, preferably independently selected from the group    consiting of H, A, Hal, CH₂Hal, CH(Hal)₂, C(Hal)₃, NO₂, (CH₂)_(n)CN,    (CH₂)_(n)OR¹¹, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)NR¹¹COR¹³,    (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A, (CH₂)_(n)SO₂NR¹¹R¹²,    (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, (CH₂)_(n)NHOA    and (CH₂)_(n)NR¹¹COOR¹³,-   h, i are independently from each other 0, 1, 2, 3, 4, 5, or 6, and-   j is 1, 2, 3, 4, 5, or 6,-   Y is selected from O, S, NR²¹, C(R²²)—NO₂, C(R²²)—CN and C(CN)₂,    wherein-   R²¹ is independently selected from the meanings given for R¹³, R¹⁴    and-   R²² is independently selected from the meanings given for R¹¹, R¹²,-   p, r are independently from one another 0, 1, 2, 3, 4 or 5,-   q is 0, 1, 2, 3 or 4, preferably 0, 1 or 2,-   u is 0, 1, 2 or 3, preferably 0, 1 or 2, and-   Hal is independently selected from a group consisting of F, Cl, Br    and I;    and the pharmaceutically acceptable derivatives, solvates, salts and    stereoisomers thereof, including mixtures thereof in all ratios, and    more preferred the salts and/or solvates thereof, and especially    preferred the physiologically acceptable salts and/or solvates    thereof.

Even more preferred are compounds of formula II

wherein

-   Ar¹, Ar² are selected independently from one another from aromatic    hydrocarbons containing 6 to 10 and especially 6 carbon atoms and    ethylenical unsaturated or aromatic heterocyclic residues containing    3 to 8 and especially 4 to 6 carbon atoms and one or two    heteroatoms, independently selected from N, O and S and especially    selected from N and O,-   R⁸, R⁹ and R¹⁰ are independently selected from a group consisting of    H, A, cycloalkyl 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂,    C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)OR¹¹, (CH₂)nNR¹¹R¹²,    (CH2)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,    (CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A,    (CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³, (CH₂)_(n)OC(O)R¹³,    (CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, (CH₂)_(n)NHOA, (CH₂)_(n)NR¹¹COOR¹³,    (CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃,    (CH₂)_(n)N(R¹¹)C(R¹³)HCOOR⁸, (CH₂)_(n)N(R¹¹), C(R¹³)HCOR⁸,    (CH₂)_(n)N(COOR¹³)COOR¹⁴, (CH₂)_(n)N(CONH₂)COOR¹³,    (CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹³)COOR¹⁴,    (CH₂)N(CH₂CONH₂)COOR¹³, (CH₂)_(n)N(CH₂CONH₂)CONH₂,    (CH₂)_(n)CHR¹³COR¹⁴, (CH₂)_(n)CHR¹³COOR¹⁴ and (CH₂)_(n)CHR¹³CH₂OR¹⁴,-   X represents a bond or is (CR¹¹R¹²)_(h), or    (CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein-   Q is selected from a group consisting of O, S, N—R¹⁵, (CHal₂)_(j),    (O—CHR¹⁸)_(j), (CHR¹⁸—O)_(j), CR¹⁸═CR¹⁹, (O—CHR¹⁸CHR¹⁹)_(j),    (CHR¹⁸CHR¹⁹—O)_(j), C═O, C═NR¹⁵, CH(OR¹⁵), C(OR¹⁵)(OR²⁰),    C(═O)N(R¹⁵), N(R¹⁵)C(═O), CH═N—NR¹⁵, S═O, SO₂, SO₂NR¹⁵ and NR¹⁵SO₂,    wherein-   h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6,    preferably 0, 1, 2 or 3 and-   j is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or 4,-   p is 1, 2, 3 or 4, preferably 1, 2 or 3, and-   r is 0, 1, 2, or 3, preferably 0, 1 or 2;    and the pharmaceutically acceptable derivatives, solvates, salts and    stereoisomers thereof, including mixtures thereof in all ratios, and    more preferred the salts and/or solvates thereof, and especially    preferred the physiologically acceptable salts and/or solvates    thereof.

Subject of the present invention are especially compounds of formula Iand II, in which one or more substituents or groups, preferably themajor part of the substituents or groups has a meaning which isindicated as preferred, more preferred, even more preferred orespecially preferred.

In compounds of formula II, the term alkyl preferably refers to anunbranched or branched alkyl residue, preferably an unbranched alkylresidue comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3,4, 5 or 6, more preferred 1, 2, 3 or 4 and especially 1 or 2 carbonatoms, or a branched alkyl residue comprising 3, 4, 5, 6, 7, 8, 9 or 10,preferably 3, 4, 5 or 6 more preferred 3 or 4 carbon atoms. The alkylresidues can be optionally substituted, especially by one or morehalogen atoms, for example up to perhaloalkyl, by one or more hydroxygroups or by one or more amino groups, all of which can optionally besubstituted by alkyl. If an alkyl residue is substituted by halogen, itusually comprises 1, 2, 3, 4 or 5 halogen atoms, depending on the numberof carbon atoms of the alkyl residue. For example, a methyl group cancomprise, 1, 2 or 3 halogen atoms, an ethyl group (an alkyl residuecomprising 2 carbon atoms) can comprise 1, 2, 3, 4 or 5 halogen atoms.If an alkyl residue is substituted by hydroxy groups, it usuallycomprises one or two, preferably one hydroxy groups. If the hydroxygroup is substituted by alkyl, the alkyl substituent comprisespreferably 1 to 4 carbon atoms and is preferably unsubstituted orsubstituted by halogen and more preferred unsubstituted. If an alkylresidue is substituted by amino groups, it usually comprises one or two,preferably one amino groups. If the amino group is substituted by alkyl,the alkyl substituent comprises preferably 1 to 4 carbon atoms and ispreferably unsubstituted or substituted by halogen and more preferredunsubstituted. According to compounds of formula II, alkyl is preferablyselected from the group consisting of methyl, ethyl, trifluoro methyl,pentafluoro ethyl, isopropyl, tert.-butyl, 2-amino ethyl,N-methyl-2-amino ethyl, N,N-dimethyl-2-amino ethyl, N-ethyl-2-aminoethyl, N,N-diethyl-2-amino ethyl, 2-hydroxy ethyl, 2-methoxy ethyl and2-ethoxy ethyl, further preferred of the group consisting of 2-butyl,n-pentyl, neo-nentyl, isopentyl, hexyl and n-decyl, more preferred ofmethyl, ethyl, trifluoro methyl, isoproply and tert.-butyl.

In compounds of formula II, alkenyl is preferably selected from thegroup consisting of allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl,furthermore preferably 4-pentenyl, isopentenyl and 5-hexenyl.

In compounds of formula II, alkylene is preferably unbranched and ismore preferably methylene or ethylene, furthermore preferably propyleneor butylene.

In compounds of formula II, alkylenecycloalkyl preferably has 5 to 10carbon atoms and is preferably methylenecyclopropyl,methylenencyclobutyl, furthermore preferably methylenecyclopentyl,methylenecyclohexyl or methylenecycloheptyl, furthermore alternativelyethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl,ethylenecyclohexyl or ethylenencycloheptyl, propylenecyclopentyl,propylenecyclohexyl, butylenecyclopentyl or butylenecyclohexyl.

In compounds of formula II, the term “alkoxy” preferably comprisesgroups of formula O-alkyl, where alkyl is an alkyl group as definedabove. More preferred, alkoxy is selected from group consisting ofmethoxy, ethoxy, n-propoxy, isopropoxy, 2-butoxy, tert.-butoxy andhalogenated, especially perhalogenated, derivatives thereof. Preferredperhalogenated derivatives are selected from the group consisting ofO—CCl₃, O—CF₃, O—C₂Cl₅, O—C₂F₅, O—C(CCl₃)₃ and O—C(CF₃)₃.

In compounds of formula II, the term “alkoxyalkyl” preferably comprisesbranched and unbranched residues, more preferred unbranched residues, offormula C_(u)H_(2u+1)—O—(CH₂)_(v), wherein u and v are independentlyfrom each other 1 to 6. Especially preferred is u=1 and v=1 to 4.

In compounds of formula II the term “alkoxyalkyl” preferably includesalkoxyalkyl groups as defined above, wherein one or more of the hydrogenatoms are substituted by halogen, for example up to perhalo alkoxyalkyl.

In compounds of formula II, cycloalkyl preferably has 3-7 carbon atomsand is preferably cyclopropyl or cyclobutyl, furthermore preferablycyclopentyl or cyclohexyl, furthermore also cycloheptyl, particularlypreferably cyclopentyl. The term “cycloalkyl”, as used herein preferablyalso includes saturated heterocyclic groups, wherein one or two carbonatoms are substituted by hetero atoms, selected from the groupconsisting of O, NH, NA and S, wherein A is as defined as above/below.

In compounds of formula II, Ar³ to Ar⁶ are preferably selectedindependently from one another from phenyl, naphthyl and biphenyl whichis optionally substituted by one or more substituents, selected from thegroup consisting of A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶,NR¹⁵CR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶, S(O)_(u)A andOOCR¹⁵.

In compounds of formula II, het is preferably an optionally substitutedaromatic heterocyclic residue and even more preferred and optionallysubstituted saturated heterocyclic residue, wherein the substituents arepreferably selected from A, CN and hal. Even more preferred, het isselected from the group consisting of 1-piperidyl, 1-piperazyl,1-(4-methyl)-piperazyl, 4-methylpiperazin-1-yl amine, 4-morpholinyl,1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-pyrazolidinyl,1-(2-methyl)-pyrazolidinyl, 1-imidazolidinyl or1-(3-methyl)-imidazolidinyl, thiophen-2-yl, thiophen-3-yl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, chinolinyl, isochinolinyl, 2-pyridazyl,4-pyridazyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazinyl and3-pyrazinyl.

In compounds of formula II, saturated heterocyclyl is preferably asubstituted or unsubstituted saturated heterocyclic residue, morepreferred an unsubstituted saturated heterocyclic residue, preferablyselected from the saturated groups given above in the definition of het.

In compounds of formula II, aromatic hydrocarbons containing 6 to 14carbon atoms and ethylenical unsaturated or aromatic heterocyclicresidues containing 3 to 10 carbon atoms and one or two heteroatoms,independently selected from N, O and S, are preferably selected from thedefinitions given herein for aryl, heteroaryl and/or het. Heteroaryl ismore preferably furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl,pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl,indolyl, indazolyl and even more preferably pyridinyl, pyrimidyl,chinolinyl, isochinolinyl, thiophenyl, thiadiazolyl, benzothiadiazolyl,oxazolyl, isoxazolyl, pyrazolyl and/or imidazolyl. Aryl more preferablyrefers to an optionally substituted benzene ring or to an optionallysubstituted benzene ring system fused to one or more optionallysubstituted benzene rings to form, for example, anthracene,phenanthrene, or napthalene ring systems. Even more preferably, aryl isselected from the group consisting of phenyl, 2-naphthyl, 1-naphthyl,biphenyl.

In compounds of formula II, Ar¹ is preferably selected from the groupconsisting of phenyl, pyridinyl, pyrimidyl, chinolinyl, isochinolinyl,thiophenyl, thiadiazolyl, benzothiadiazolyl, oxazolyl, isoxazolyl,pyrazolyl and imidazolyl, and especially from phenyl, pyridinyl,chinolinyl, isochinolinyl, thiophenyl, benzothiadiazolyl, oxazolyl,isoxazolyl and oxazolyl.

Preferably, the sum of h and l exceeds 0.

A preferred aspect of the instant invention relates to compounds offormula II, wherein n is 0 or 1 and especially 0.

Another preferred aspect of the instant invention relates to compoundsof formula II, wherein n is 0 in the residues R⁸, R⁹ and/or R¹⁰ andespecially in R¹⁰.

Another preferred aspect of the instant invention relates to compoundsof formula II, wherein X represents a bridging group, selected from(CR¹¹R¹²)_(h) or (CHR¹¹)_(h)-Q-(CHR¹²)_(i).

The invention relates in particular to compounds of the formula II inwhich at least one of said radicals has one of the preferred meaningsgiven above/below.

Some more preferred groups of compounds may be expressed by thefollowing sub-formulae II.1) to II.20), which correspond to the formulaII and in which radicals not denoted in greater detail are as defined inthe formula II, but in which

-   II.1) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl;-   II.2) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl, and    -   p is 1, 2 or 3;-   II.3) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3, and    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³;-   II.4) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³;-   II.5) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³ (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1;-   II.6) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³ (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1, and    -   q is 0 or 1;-   II.7) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹² (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³ (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S;-   II.8) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl;-   II.9) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²;-   II.10) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2;-   II.11) Ar¹ is phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or    imidazolyl, preferably phenyl, pyridinyl or isoxazolyl and    especially phenyl or oxazolyl,    -   p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₁₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.12) p is 1, 2 or 3,    -   R⁸ is selected from the group consisting of alkyl comprising 1        to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.13) R⁸ is selected from the group consisting of alkyl comprising    1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,    CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,    (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,    (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   n is 0, 1 or 2, preferably 0 or 1,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.14) R⁸ is selected from the group consisting of alkyl comprising    1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,    CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,    (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹² (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,    (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.15) R⁸ is selected from the group consisting of alkyl comprising    1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,    CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,    (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,    (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    -   q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.16) q is 0 or 1, and    -   X is selected from the group consisting of O, S, NR¹¹, CHOR¹¹,        CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S and        CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³ preferably selected        from the group consisting of alkyl comprising 1 to 4 carbon        atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.17) X is selected from the group consisting of O, S, NR¹¹,    CHOR¹¹, CH₂, CH₂CH₂, OCH₂, CH₂O, OCH₂CH₂, CH₂CH₂O, preferably O, S    and CH₂ and especially O and S,    -   Ar² is phenyl, pyridinyl or pyrimidyl, and especially is phenyl        or pyridinyl, and    -   R¹⁰ is selected from the group consisting of H, alkyl comprising        1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,        CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms,        NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,        (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³, preferably        selected from the group consisting of alkyl comprising 1 to 4        carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,        (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and        especially (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.18) Ar² is phenyl, pyridinyl or pyrimidyl, and especially is    phenyl or pyridinyl, and-   R¹⁰ is selected from the group consisting of alkyl comprising 1 to 4    carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH₂Hal,    CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon atoms, NO₂,    (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹²,    (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³ preferably selected    from the group consisting of alkyl comprising 1 to 4 carbon atoms,    (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³,    (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially    (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.19) R¹⁰ is selected from the group consisting of H, alkyl    comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon    atoms, Hal, CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon    atoms, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹“R¹²,    (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³,    (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    preferably selected from the group consisting of alkyl comprising 1    to 4 carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially    (CH₂)_(n)CONR¹¹R¹²,    -   k is 0, 1 or 2, preferably 0 or 2 and    -   r is 0, 1 or 2, preferably 0 or 1;-   II.20) R¹⁰ is selected from the group consisting of H, alkyl    comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon    atoms, Hal, CH₂Hal, CH(Hal)₂, perhaloalkyl comprising 1 to 4 carbon    atoms, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹²,    (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³,    (CH₂)_(n)CONR¹¹R¹², (CH₂)_(n)SO₂NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³,    preferably selected from the group consisting of alkyl comprising 1    to 4 carbon atoms, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,    (CH₂)_(n)COR¹³, (CH₂)_(n)COOR¹³, (CH₂)_(n)CONR¹¹R¹² and especially    (CH₂)_(n)CONR¹¹R¹², and    -   r is 0, 1 or 2, preferably 0 or 1.

One preferred embodiment of the instant invention relates to compoundsof formula II and preferably one or more of sub formulae II.1) toII.20), wherein p is 1, 2 or 3 and R⁸ is independently selected from thegroup consisting of methyl, ethyl, isopropyl, tert.-butyl, F, Cl, Br,CF₃, C(CF₃)₃, methoxy, ethoxy, tert.-butoxy, perfluoro tert.-butoxy(OC(CF₃)₃), methyl sulfanyl (SCH₃), ethyl sulfanyl (SCH₂CH₃), acetyl(COCH₃), propionyl (COCH₂CH₃), butyryl (COCH₂CH₂CH₃) and SO₂CF₃. If p is2 or 3, all substituents can be the same or different.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein X is selected from the group consisting of S, N—R²¹,CH₂, CH₂CH₂, OCH₂, CH₂O, C═O, C(═O)—NH and NH—C(═O).

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein X is selected from the group consisting of S, CH₂.

Another even more preferred embodiment of the instant invention relatesto compounds of formula II and preferably one or more of sub formulaeII.1) to II.20), wherein X is O.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Y is selected from the group consisting ofC(R²²)—NO₂, C(R²²)—CN and C(CN)₂.

Another more preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Y is selected from the group consisting of O, S andNR²¹.

Another even more preferred embodiment of the instant invention relatesto compounds of formula II and preferably one or more of sub formulaeII.1) to II.20), wherein Y is selected from the group consisting of Oand S.

Another even more preferred embodiment of the instant invention relatesto compounds of formula II and preferably one or more of sub formulaeII.1) to II.20), wherein Y is O.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar² is pyridinyl.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein r is either 0 or 1. If r is 1, R¹⁰ is preferably(CH₂)_(n)CONR¹¹R¹² and especially (CH₂)_(n)CONR¹¹R¹², wherein n is 0. Inthis embodiment, R¹¹ is preferably selected from the group consisting ofH and A, more preferred from H and alkyl and especially is H, and R¹² ispreferably selected from the group consisting of H and A and morepreferred from H, unsubstituted alkyl and substituted alkyl, preferablycomprising 1 to 6 and especially 1 or 2 carbon atoms. Suitable forsubstituents include amino groups, such as NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂and NH(CH₂CH₃), and carboxyl groups and derivatives thereof, such asCOOH, COOCH₃, CONH₂, and CONHCH₃. Especially preferred as residue R¹⁰are CONHCH₃, CONHCH₂CH₂NH₂, CONHCH₂CH₂NHCH₃, CONHCH₂CH₂N(CH₃)₂,CONHCH₂COOH and CONHCH₂CH₂COOH. This embodiment is especially preferredwhen Ar² is pyridinyl. When Ar² is pyridinyl, R¹⁰ is preferably bondedin a vicinal position to the nitrogen atom of the pyrindiyl residue,i.e. in 2- and/or 6-position of the pyridinyl residue.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar¹ comprises two or more substituents R⁸, whereinone or more, preferably one substituent R⁸ is selected from the groupconsisting of (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², (CH₂)_(n)NR¹¹(CH₂)_(k)NR¹²R¹²,(CH₂)_(n)COOR¹³ and (CH₂)_(n)S(O)_(u)R¹³ wherein R¹¹, R¹² and R¹³ aredefined as above and n is as defined above, preferably n is 0, 1 or 2and especially is 0, k is 1 to 4 and preferably 1 or 2, and u ispreferably 2. In this embodiment R¹¹, R¹² and R¹³ are more preferablyselected independently from each other from the group consisting of H,methyl and ethyl. In this embodiment, one or two substituents R⁸ andpreferably one substituent R⁸ is especially preferably selected from thegroup consisting of NH₂, N(CH₃)₂, N(C₂H₅)₂, NHCH₂CH₂NH₂,N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂,N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅, SO₂CH₃, COOCH₃ and COOH.Accordingly, in this embodiment Ar¹ especially preferably comprises atleast one substituent R⁸ other than (CH₂)_(n)NR¹¹R¹²,(CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)NR¹¹(CH₂)_(k)OR¹²,(CH₂)_(n)NR¹¹(CH₂)_(k)NR¹²R¹², (CH₂)_(n)COOR¹³ and (CH₂)_(n)S(O)_(u)R¹³as defined in this paragraph and especially other than NH₂, N(CH₃)₂,N(C₂H₅)₂, NHCH₂CH₂NH₂, N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂,N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅,SO₂CH₃, COOCH₃ and COOH.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein q is 1, i.e. the phenylen moiety bound to the oxamidegroup and the radical X is substituted once, preferably by a substituentselected from the group consisting of alkyl and halogen and morepreferred from methyl, ethyl, F, Cl and Br.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein q is 0, i.e. the phenylen moiety bound to the oxamidegroup and the radical X is unsubstituted.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of formulae II.1) toII.20), wherein (R⁸)_(p)—Ar¹ is selected from the group consisting of3-acetyl-phenyl, 4-acetyl-phenyl, 2-bromo-phenyl, 3-bromo-phenyl,4-bromo-phenyl, 4-bromo-2-chloro-phenyl, 4-bromo-3-methyl-phenyl,4-bromo-3-trifluoromethyl-phenyl, 2-chloro-phenyl,2-chloro-4-trifluoromethyl-phenyl, 2-chloro-5-trifluoromethyl-phenyl,3-chloro-phenyl, 3-chloro-4-methyl-phenyl, 3-chloro-4-methoxy-phenyl,3-chloro-4-methoxy-phenyl, 4-chloro-phenyl,4-chloro-2-trifluoromethyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl,4-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl,5-chloro-2-methoxy-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl,4-chloro-2-methoxy-5-trifluoromethyl-phenyl, 2,3-dichloro-phenyl,2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 3,4-dichloro-phenyl,3,5-dichloro-phenyl, 2,4,5-trichloro-phenyl, 4-fluoro-phenyl,4-fluoro-3-trifluoromethyl-phenyl, 4-ethoxy-phenyl, 2-methoxy-phenyl,2-methoxy-5-trifluoromethyl-phenyl, 4-methoxy-phenyl,2,5-dimethoxy-phenyl, 2-trifluoromethyl-phenyl,3-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl,4-trifluoromethyl-phenyl, 4-trifluoromethoxy-phenyl,3,5-bis-trifluoromethyl-phenyl, 3-methoxy-phenyl,3-methylsulfanyl-phenyl, 4-methylsulfanyl-phenyl, o-tolyl(2-methyl-phenyl), m-tolyl (3-methyl-phenyl), p-tolyl (4-methyl-phenyl),2,3-dimethyl-phenyl, 2,3-di-methyl-phenyl, 2,5-dimethyl-phenyl,3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl, 2-ethyl-phenyl,3-ethyl-phenyl, 4-ethyl-phenyl, 4-isopropyl-phenyl, 4-tert-butyl-phenyland 5-tert-butyl-isoxazol-3-yl.

Another preferred embodiment of the instant invention relates tocompounds of formula II and the subformulae related thereto andpreferably one or more of formulae II.1) to II.20), wherein the residues(R⁸)_(p)—Ar¹ are selected from the group consisting of componds of thefollowing formulae:

and/or residues of the structures given above that comprise one or two,preferably one additional substituent, independently selected from themeanings given for R⁸.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein (R⁸)_(p)—Ar¹ is as defined above, but comprises oneor more additional residues, preferably one additional residue. Theadditional residues are preferably selected from the meanings given forR⁸ and more preferably selected from the group consisting of(CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², (CH₂)_(n)NR¹¹(CH₂)_(k)NR¹¹R¹²,(CH₂)_(n)COOR¹³, (CH₂)_(n)S(O)_(u)NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³wherein R¹¹, R¹² and R¹³ are defined as above and n is as defined above,preferably n is 0, 1 or 2 and especially is 0, k is 1 to 4 andpreferably 1 or 2, and u is preferably 2. In this embodiment R¹¹, R¹²and R¹³ are more preferably selected independently from each other fromthe group consisting of H, methyl and ethyl. Even more preferred, theadditional residue(s) is/are selected from the group consisting of NH₂,N(CH₃)₂, N(C₂H₅)₂, NHCH₂CH₂NH₂, N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂,N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅,SO₂CH₃, SO₂CF₃, OSO₂CH₃, OSO₂CF₃, SO₂NH₂, SO₂NHCH(CH₃)₂, SO₂N(CH₃)₂,SO₂N(CH₂CH₃)₂, 4-Morpholino-sulfonyl, COOCH₃ and COOH.

Another preferred embodiment of the instant invention relates tocompounds of formula II and the subformulae related thereto andpreferably one or more of formulae II.1) to II.20), wherein the residuesAr²-(R¹⁰)_(r) are selected from the group consisting of componds of thefollowing formulae:

and/or residues of the structures given above that comprise one or two,preferably one additional substituent, independently selected from themeanings given for R¹⁰.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein (R⁸)_(p)—Ar¹ is as defined above, but comprises oneor more additional residues, preferably one additional residue. Theadditional residues are preferably selected from the meanings given forR⁸ and more preferably selected from the group consisting of(CH₂)_(n)NR¹¹R¹², (CH₂)_(n)O(CH₂)_(k)NR¹¹R¹²,(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹², (CH₂)_(n)NR¹¹(CH₂)_(k)NR¹²R¹²,(CH₂)_(n)COOR¹³ and (CH₂)_(n)S(O)_(u)R¹³ wherein R¹¹, R¹² and R¹³ aredefined as above and n is as defined above, preferably n is 0, 1 or 2and especially is 0, k is 1 to 4 and preferably 1 or 2, and u ispreferably 2. In this embodiment R¹¹, R¹² and R¹³ are more preferablyselected independently from each other from the group consisting of H,methyl and ethyl. Even more preferred, the additional residue(s) is/areselected from the group consisting of NH₂, N(CH₃)₂, N(C₂H₅)₂,NHCH₂CH₂NH₂, N(CH₃)CH₂CH₂NH₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂,N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, SCH₃, SC₂H₅, SO₂CH₃, COOCH₃ and COOH.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein X is bonded in the para- (p-) or metha- (m-)positionto the phenyl residue that is bonded directly to the oxamide moiety.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar² is a pyridinyl residue and wherein said pyridinylresidue is bonded to X in the 3- or 4-position, preferably the4-position, relative to the nitrogen atom of the pyridinyl residue.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar² comprises one or more substituents R¹⁰ andwherein one or two, preferably one substituent R¹⁰ is selected fromunsubstituted or substituted carbamoyl moieties. Substituted carbamoylmoieties are preferably selected from CONHR²³ or CONR²³R²⁴, preferablyCONHR²³, wherein R²³ and R²⁴ are independently selected from thedefinitions given for R⁸, more preferably selected from alkyl,preferably methyl, ethyl, propyl and butyl, (CH₂)_(n)NR¹¹R¹² and(CH₂)_(n)OR¹², wherein R¹¹, R¹² and n are as defined above. In thisembodiment, n is preferably not 0 and more preferred 1 to 3 andespecially 1 or 2. Preferred examples for R²³ are selected from thegroup consisting of methyl, ethyl, CH₂CH₂NH₂, CH₂CH₂N(CH₃)₂,CH₂CH₂N(CH₂CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ and CH₂CH₂OCH₂CH₃.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar² comprises one or more substituents R¹⁰ andwherein one or two, preferably one substituent R¹⁰ is selected fromsubstituted carbamoyl moieties. Substituted carbamoyl moieties arepreferably selected from CONHR²³, wherein R²³ is preferablyunsubstituted C₁-C₄-alkyl and especially methyl.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar² comprises one or more substituents R¹⁰ andwherein one or two, preferably one substituent R¹⁰ is selected fromsubstituted carbamoyl moieties. Substituted carbamoyl moieties arepreferably selected from CONHR²³, wherein R²³ is selected from(CH₂)_(n)NR¹¹R¹² and (CH₂)_(n)OR¹² wherein R¹¹, R¹² and n are as definedabove. In this embodiment, n is preferably not 0 and more preferred 1 to3 and especially 1 or 2. Preferred examples for R²³ are selected fromthe group consisting of CH₂CH₂NH₂, CH₂CH₂N(CH₃)₂, CH₂CH₂N(CH₂CH₃)₂,CH₂CH₂OH, CH₂CH₂OCH₃ and CH₂CH₂OCH₂CH₃.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein Ar¹ comprises one or more substituents R⁸ and whereinone or two, preferably one substituent R⁸ is selected from the groupconsisting of NH₂, N(CH₃)₂, NHCH₃, N(C₂H₅)₂, HNCH₂CH₂NH₂, OCH₂CH₂NH₂,HOCH₂CH₂NH, OCH₂CH₂NHCH₃, N(CH₃)CH₂CH₂NH₂, HN(CH₃)CH₂CH₂NH,N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃,OCH₂CH₂N(CH₃)₂, OCH₂CH₂N(CH₂CH₃)₂, SCH₃, SC₂H₅, and compounds of theformulae

and/or Ar² comprises one or more substituents R¹⁰ and wherein one ortwo, preferably one substituent R¹⁰ is independently selected from themeanings given for R⁸ in this paragraph.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20), wherein —Ar²-(R¹⁰)_(r) is selected from the formulae

wherein R¹⁰, R²³ and R²⁴ are as defined above and below.

Another especially preferred embodiment of the instant invention relatesto compounds of formula II and preferably one or more of sub formulaeII.1) to II.20), wherein one or more features of the above and belowmentioned embodiments are combined in one compound.

Subject of the present invention are therefore especially preferredcompounds of formula II according to one or more of the formulae IIa,IIb, IIc, IId, IIe IIf, IIg and IIh,

wherein R⁸, p, X, Y, R⁹ and q are as defined above and below, and R¹⁰ isH or as defined above and below, and preferably all are as defined insub formulae II.1) to II.20) and/or the embodiments related thereto.

Another preferred embodiment of the instant invention relates tocompounds of formula II and preferably one or more of sub formulae II.1)to II.20) and IIa to IIh, wherein R¹⁰ is a substituted carbamoyl moietyCONHR²³ or CONR²³R²⁴, preferably CONHR²³, wherein R²³ and R²⁴ areindependently selected from the definitions given for R⁸, morepreferably selected from (CH₂)_(n)NR¹¹R¹² and (CH₂)_(n)OR¹², whereinR¹¹, R¹² and n are as defined above. In this embodiment, n is preferablynot 0 and more preferred 1 to 3 and especially 1 or 2. Preferredexamples for R²³ are selected from the group consisting of CH₂CH₂NH₂,CH₂CH₂N(CH₃)₂, CH₂CH₂N(CH₂CH₃)₂, CH₂CH₂OH, CH₂CH₂OCH₃ and CH₂CH₂OCH₂CH₃.

It is understood that when a residue, for example R⁸, R⁹, R¹⁰ or R¹⁴ orR²³, is comprised twice or more times in one or more of the formulae I,II and the sub formulae corresponding thereto, it is in each caseindependently from one another selected from the meanings given for therespective residue. For example, R¹¹ and R¹² are defined to beindependently selected from a group consisting of H, A, (CH₂)_(m)Ar³ and(CH₂)_(m)Het. Then (CH₂)_(n)NR¹¹(CH₂)_(m)NR¹²R¹² can be(CH₂)_(n)NA(CH₂)_(m)NA₂ (if R¹¹=A, R¹²=A and R¹²=H) as well as(CH₂)_(n)NA(CH₂)_(m)NHA (if R¹¹=A, R¹²=H and R¹²=A or(CH₂)_(n)NA(CH₂)_(m)NH(CH₂)_(m)Het (if R¹¹=A, R¹²=H andR¹²=(CH₂)_(m)Het). Accordingly, if a compound of formula II comprisesone residue R⁸, R⁹ and R¹⁰, then for example R⁸, R⁹ and R¹⁰ can all be(CH₂)_(n)COOR¹³, wherein all residues R¹³ are the same (for exampleCH₂Hal, wherein Hal is Cl; then all residues R⁸, R⁹ and R¹⁰ are thesame) or different (for example CH₂Hal, wherein in R⁸ Hal is Cl; in R⁹Hal is F; and in R¹⁰ Hal is Br; then all residues R⁸, R⁹ and R¹⁰ aredifferent); or for example R⁸ is (CH₂)_(n)COOR¹³, R⁹ is NO₂ and R¹⁰ is(CH₂)_(n)SR¹¹, wherein R¹¹ and R¹³ can be the same (for example both canbe H or both can be A which is methyl) of different (for example R¹¹ canbe H and R¹³ can be A which is methyl).

If not stated otherwise, reference to compounds of formula I and formulaII also includes the sub formulae related thereto, especially subformulae II.1) to II.20) and IIa to IIh.

Subject of the instant invention are especially those compounds offormula I and/or formula II, in which at least one of the residuesmentioned in said formulae has one of the preferred or especiallypreferred meanings given above and below.

The present invention further relates to compounds (1) to (224) offormula A-NH—CO—CO—NH-B, wherein A and B are as given in the tablebelow: A B (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organisation for chemical compounds and especially organiccompounds.

In a special embodiment, one or more of the oxamide derivativesaccording to sub formulae IIa to IIh and/or compounds (1) to (224)additionally comprise one or two substituents selected from the groupconsisting of O(CH₂)_(n)NR¹¹R¹², NR¹¹(CH₂)_(n)NR¹¹R¹², O(CH₂)_(n)OR¹²and NR¹¹(CH₂)_(n)OR¹²,

wherein

-   -   R¹¹, R¹² are independently selected from a group consisting of        H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het, or in NR¹¹R¹²,    -   R¹¹ and R¹² form, together with the N-Atom they are bound to, a        5-, 6- or 7-membered heterocyclus which optionally contains 1 or        2 additional hetero atoms, selected from N, O an S, and    -   n is 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

In this special embodiment, the substituents are preferably selectedfrom the group consisting of HNCH₂CH₂NH₂, OCH₂CH₂NH₂, NHCH₂CH₂OH,OCH₂CH₂NHCH₃, N(CH₃)CH₂CH₂NH₂, HN(CH₃)CH₂CH₂NH, N(CH₃)CH₂CH₂N(CH₃)₂,N(CH₃)CH₂CH₂N(CH₃)₂, N(CH₃)CH₂CH₂OCH₃, OCH₂CH₂N(CH₃)₂, OCH₂CH₂N(CH₂CH₃)₂and compounds of the formulae

and/or compounds of formulae

In a further special embodiment, one or more of the oxamide derivativesaccording to sub formulae IIa to IIh and/or compounds (1) to (224)additionally comprise one or two substituents selected from the groupconsisting of (CH₂)_(n)S(O)_(u)NR¹¹R¹² and (CH₂)_(n)S(O)_(u)R¹³ whereinR¹¹, R¹² and R¹³ are defined as above and n is as defined above,preferably n is 0, 1 or 2 and especially is 0, and u is preferably 2 or3. In this embodiment, the residues are preferably selected from SO₂CH₃,SO₂CF₃, OSO₂CH₃, OSO₂CF₃, SO₂NH₂, SO₂NHCH(CH₃)₂, SO₂N(CH₃)₂,SO₂N(CH₂CH₃)₂ and 4-Morpholino-sulfonyl.

In this special embodiments, the additional substituents are preferablybound to one of the aromatic residues directly bound to the oxamidemoiety and/or the pyridinyl residue. More preferably, one or twoadditional substituents are bound to the residue Ar¹ according toformula II. Even more preferably, in one or more of the formulae IIa toIId, one or two additional substituents are bound to the phenyl moietydirectly bound to the N-nitrogen atom of the oxamide moiety, i.e. thephenyl moiety at the left hand side of the respective formulae.Especially preferred are compounds (1) to (224), wherein one or twoadditional substituents are bound to the moiety A.

Another aspect of the invention relates to a method for producingcompounds of formula II, characterised in that

-   a) A compound of formula III    -   wherein    -   L¹ is Cl, Br, I, OH, an esterified OH-group or a diazonium        moiety, and R⁸, p, Ar¹, Y are as defined above and below,    -   is reacted-   b) with a compound of formula IV,    -   wherein    -   L², L³ are independently from one another H or a metal ion, and        R⁹, q, X, Ar², R¹⁰ and r are as defined above and below,    -   and optionally-   c) isolating and/or treating the compound of formula II obtained by    said reaction with an acid, to obtain the salt thereof.

The compounds of the formula I and preferably the compounds of theformula II and also the starting materials for their preparation are, inaddition, prepared by methods known per se, as described in theliterature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditionswhich are known and suitable for the said reactions. Use can also bemade here of variants which are known per se, but are not mentioned herein greater detail.

If desired, the starting materials can also be formed in situ by notisolating them from the reaction mixture, but instead immediatelyconverting them further into the compounds of the formula I or II,respectively. On the other hand, it is possible to carry out thereaction stepwise.

The compounds of the formula I and especially the compounds of formulaII can preferably be obtained by reacting compounds of the formula IIIwith compounds of the formula IV.

In detail, the reaction of the compounds of the formula III with thecompounds of the formula IV is carried out in the presence or absence ofa preferably inert solvent at temperatures between about −20° and about200°, preferably between 0° and 150° and especially between roomtemperature (25°) and 120°. In some cases, it can be advantageous tocombine one compound of formula III with one compound of formula IV atthe lower end of the given temperature range, preferably between −20°and 75°, more preferred between 0° and 60° and especially between 100and 40°, for example at about room temperature, and heat the mixture upto a temperature at the upper end of the given temperature range,preferably between 80° and 180°, more preferred between 90° and 150° andespecially between 95° and 120°, for example at about 100° or at about110°.

In general, the compounds of formula III and/or formula IV are new. Inany case, they can be prepared according to methods known in the art.

In the compounds of formula III, L¹ is preferably Cl, Br, I, OH, areactive derivatized OH-moiety, especially an esterified OH-moiety, forexample an OR′-moiety wherein R′ is an alkyl moiety, preferably an alkylmoiety as described above/below comprising 1 to 10 and more preferably 1to 6 carbon atoms, or a reactive esterified OH-moiety, for example analkylsulfonyloxy-moiety comprising 1 to 6 carbon atoms (preferablymethylsulfonyloxy) or an arylsulfonyloxy-moiety comprising 6 to 10carbon atoms (preferably phenyl-oder p-tolylsulfonyloxy), or diazoniummoiety, more preferred Cl, Br or I and OR′, wherein R′ is as definedabove/below, and even more preferred OH and OR′, wherein R′ ispreferably selected from the group consisting of methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. Especially preferredas L¹ is OH.

In the compounds of formula IV, L² and/or L³ is preferably H or a moietywhich activates the amino group it is bonded to, for example a metalion. Suitable metal ions are preferably selected from the groupconsisting of alkaline metal ions, alkaline-earth metal ions andaluminium ions. Especially preferred metal ions are alkaline metal ions,of which Li, Na and/or K are especially preferred. In case ofmulti-valent metal ions, the metal ions and the compounds of formula IVform a complex containing one or more compounds of formula IV and one ormore metal ions wherein the ratio between compounds of formula IV andmetal ions is depending on the valency of the metal ion(s) according tothe rules of stoichiometry and/or electroneutrality.

The reaction between the compounds of formula III and compounds offormula IV can in many cases advantageously be carried out in thepresence of an acid binding means, for example one or more bases.Suitable acid binding means are known in the art. Preferred as acidbinding means are inorganic bases and especially organic bases. Examplesfor inorganic bases are alkaline or alkaline-earth hydroxides, alkalineor alkaline-earth carbonates and alkaline or alkaline-earth bicarbonatesor other salts of a weak acid and alkaline or alkaline-earth metals,preferably of potassium, sodium, calcium or cesium. Examples for organicbases are triethyl amine, diisopropyl ethyl amine (DIPEA), dimethylaniline, pyridine or chinoline. If an organic base is used, it isadvantageous in general to use a base with a boiling point that ishigher than the highest reaction temperature employed during thereaction. Especially preferred as organic base is diisopropyl ethylamine.

Reaction times are generally in the range between some minutes andseveral days, depending on the reactivity of the respective compoundsand the respective reaction conditions. Suitable reaction times arereadily determinable by methods known in the art, for example reactionmonitoring. Based on the reaction temperatures given above, suitablereaction times generally lie in the range 10 min and 36 hrs, preferably30 min and 24 hrs and especially between 45 min and 16 hrs, for exampleabout 2 h, about 6 hrs, about 10 hrs or about 14 hrs.

Preferably, the reaction of the compounds of the formula III with thecompounds of the formula IV is carried out in the presence of a suitablesolvent, that is preferably inert under the respective reactionconditions. Examples of suitable solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichlorethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone(NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents. Polarsolvents are in general preferred. Examples for suitable polar solventsare chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amidesand sulfoxides or mixtures thereof. More preferred are amides,especially dimethylformamide (DMF).

If compounds of formula II are desired wherein Y is other than O, it canbe advantageous, however, to carry out the reaction of a compound offormula III, wherein Y is O, and a compound of formula IV according tothe invention to obtain a compound of formula II, wherein Y is O, and tomodify or convert the corresponding C═O group (i.e. the C═Y group,wherein Y is O) in the compound of formula II into a C═NR²¹,C═C(R²²)—NO₂, C═C(R²²)—CN or C═C(CN)₂ group according to methods knownin the art, for example from Houben-Weyl, Methods of Organic Chemistry.

The compounds of formula III can be obtained according to methods knownin the art. In an advantageous manner, they can be readily obtained byreacting a compound of formula V

wherein R⁸, p, and Ar¹ are as defined above/below and L⁴ and L⁵ areselected independently from each other from the meanings given for L²and L³ and more preferred are hydrogen, with a compound of formula VI

wherein each Y is independently from one another as defined above/belowand L⁶ and L⁷ are selected independently from each other from themeanings given for L¹. Preferably, one of L⁶ and L⁷ is halogen and oneof L⁶ and L⁷ is an OH-moiety and more preferred a derivatized OH-moiety.Preferably, derivatized OH-moieties are OR′-moieties, wherein R′ isselected from the meanings given above/below. More preferred, L⁶ isselected from the group consisting of Cl, Br and I. Especiallypreferred, L⁶ is Cl. L⁷ is more preferred an OH-moiety and even morepreferred a derivatized OH-moiety as defined above. Especiallypreferred, L⁷ is an OR′-moiety, wherein R′ is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andt-butyl, and especially is OCH₂CH₃.

If L¹ in the compounds of formula III is OR′, wherein R′ is as definedabove, it is in many cases advantageous, to transfer said compound intoa compound of formula III, wherein L¹ is OH before reacting it with acompound of formula IV. Methods for transferring a compound of formulaIII, wherein L¹ is OR′ as defined above, into a compound of formula III,wherein L¹ is OH are known in the art, for example ester cleavages. Anester cleavage can be carried out in an acidic or basic medium accordingto methods known per se. Preferably an ester cleavage is carried out ina basic medium, for example in the presence of one or more bases,preferably inorganic bases such as alkaline or alkaline-earthhydroxides, more preferably NaOH or KOH, in a preferably polar solventsuch as water or alcohol, for example alcohols as described above/below,or mixtures thereof. Suitable reaction temperatures usually lie in therange between 0° C. and the boiling point of the solvent chosen andespecially at about room temperature.

Some of the starting materials of the formula V and/or the formula VIare known and preferably commercially available. If they are not known,they can be prepared by methods known per se.

Suitable reaction conditions for carrying out the reaction of a compoundof formula V with a compound of formula VI are known in the art. Indetail, the reaction of the compounds of the formula V with thecompounds of the formula VI is carried out in the presence or absence ofa preferably inert solvent and in the presence or absence of a suitablebase at temperatures between about −40° and about 180°, preferablybetween −20° C. and 100° and especially between −10° and 50°, forexample at about 0° and/or about room temperature (25°).

The reaction between compounds of formula V and compounds of formula VIis preferably carried out in the presence of an acid binding means, forexample one or more bases. Suitable acid binding means are known in theart. Preferred as acid binding means are inorganic bases and especiallyorganic bases. Examples for inorganic bases are alkaline oralkaline-earth hydroxides, alkaline or alkaline-earth carbonates andalkaline or alkaline-earth bicarbonates or other salts of a weak acidand alkaline or alkaline-earth metals, preferably of potassium, sodium,calcium or cesium. Examples for organic bases are triethyl amine,diisopropyl ethal amine (DIPEA), dimethyl aniline, pyridine orchinoline. If an organic base is used, it is advantageous in general touse a base with a boiling point that is higher than the highest reactiontemperature employed during the reaction. Especially preferred asorganic base is DIPEA.

The reaction between compounds of formula V and compounds of formula VIcan be carried out in the presence of a suitable solvent, that ispreferably polar and preferably inert at the chosen reaction conditions.Suitable solvents are known in the art. Examples for suitable polarsolvents are chlorinated hydrocarbons, alcohols, glycol ethers,nitriles, amides and sulfoxides or mixtures thereof. More preferred areamides, especially preferred is dimethylformamide (DMF).

In many cases, it is advantageous to carry out the reaction of acompound of formula V with a compound of formula VI in the presence ofone or more compounds that promote the reaction between the saidcompounds, for example one or more catalysts and/or one or morecompounds that are acting as condensing agents. Suitable compounds inthis respect are O-(Benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphat tetrafluoroborate (TBTU),O-(Benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborateand 1-Hydroxy-1H-benzotriazole (HOBT).

Especially preferred, the reaction between a compound of formula V,wherein L⁴ and L⁵ preferably are hydrogen, and a compound of formula VI,wherein preferably Y both are O and wherein L⁶ is halogen and L⁷ is OH,is carried out in the presence of an organic base, such as DIPEA, apolar organic solvent, such as DMF, in the presence of TBTU and HOBT ata temperature between 0° C. and 60° C., for example at about roomtemperature.

The compounds of formula IV can be obtained according to methods knownin the art.

If the compound of formula IV is a compound according to formula IVa,

it can be readily obtained in an advantageous manner by reacting acompound of formula VIIa,

wherein R⁹ and q are as defined above/below,with a compound of formula VIII,L⁸-X—Ar²-(R¹⁰)_(r)  VIIIwherein L⁸ is H or a metal ion, preferably a metal ion selected from thegroup consisting of alkaline metal ions, alkaline-earth metal ions andaluminum ions, especially preferred alkaline metal ions, of which Li, Naand K are especially preferred, and even more preferred is H; and Ar²,R¹⁰, r and X are as defined above/below, and especially wherein X is(CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein R¹¹, h and R¹² are definedabove/below, i is 0 and Q is selected from a group consisting of O, S,N—R¹⁷, (CHR¹⁸—O)_(j), (CHR¹⁸CHR¹⁹—O)_(j), CH═N—O, CH═N—NR¹⁷, SO₂NR¹⁷,wherein R¹⁷, R¹⁸ and R¹⁹ are as defined above/below;optionally isolating the reaction product,and transferring the obtained reaction product of formula IX

into a compound of formula IVa, preferably by hydrogenating theNO₂-moiety of the compound of formula IX into a NH₂-moiety. Methods andreaction conditions for hydrogenating said NO₂-moiety into a NH₂-moietyare known in the art. In general, it is advantageous to carry out thehydrogenation reaction in a hydrogen atmosphere in the presence of asuitable catalyst, preferably a Palladium catalyst, for example Pd/C. Ingeneral, such hydrogenation reactions are carried out in a suitablesolvent. Suitable solvents for hydrogenation reactions are known in theart. Suitable solvents, for example, are alcohols, especially methanoland ethanol and ethers, especially THF, and mixtures thereof. Ingeneral, the hydrogenation reactions are carried out at about normalpressure or slightly elevated pressure, for example between normalpressure and 3 bar pressure (about 300 kPa). The hydrogenation reactionis usually carried out in the temperature range between −20° and 150°,preferably 0° and 50°.

Ar² is preferably pyridinyl. Accordingly, the compound of formula VIIIis preferably selected from the group consisting of formulae VIIIa andVIIIb,

wherein L⁸, X, R¹⁰ and r are as defined above, and especially preferredfrom the group consisting of formulae VIIIc and VIIId,

wherein R¹⁰ and r are as defined above, or the alkaline metal salts andespecially the sodium or potassium salts thereof.

Accordingly, in formulae IVa, VIII, VIIIa, VIIIb and IX, the bridginggroup X is preferably O, S, OCH₂ and OCH₂CH₂ and especially is O.

In the formulae VIII, VIIIa and VIIIb, L⁸ is preferably H or selectedfrom the group consisting of Na, K and Cs and especially preferred is H.

In general, this reaction is advantageous to produce compounds offormula IVaa,

wherein R⁹, q, X, Ar², R¹⁰ and r are as defined above/below.

To obtain compounds of formula IVaa, it is reasonable to employ acompound of formula VII that is selected from the compounds of formulaVIIa,

and proceed the reaction as described above/below.

Accordingly, by starting from a compound of formula VIIa and a compoundof formula VIIIa, the reaction preferably leads to compounds of formulaIVaaa,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIa and a compoundof formula VIIIb, the reaction preferably leads to compounds of formulaIVaab,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIa and a compoundof formula VIIIc, the reaction preferably leads to compounds of formulaIVaac,

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIa and a compoundof formula VIIId, the reaction preferably leads to compounds of formula

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Some of the starting materials of the formula VII and/or the formulaVIII are known and preferably commercially available. If they are notknown, they can be prepared by methods known per se.

The reaction between the compound of formula VII and VIII is preferablycarried out in the temperature range between 0° and 250°, more preferredroom temperature and 200°, for example at about 120°, at about 150° orat about 180°. Reaction times depend on the respective reactants and therespective reaction temperature, but generally lie in the range between30 min and 36 hrs, preferably 3 hrs and 24 hrs, more preferably 8 hrsand 20 hrs for example about 10 hrs, about 16 hrs or about 18 hrs.

The reaction can be carried out in the absence of solvent or preferablyin the presence of an solvent, preferable a solvent that is inert underthe respective reaction conditions. Suitable inert solvents for carryingout the reaction are known in the art. Examples for suitable solventsare high boiling aliphatic hydrocarbons, high boiling aromatic carbons,for example toluene, xylenes, high boiling chlorinated hydrocarbons,such as trichloroethylene, tetrachloroethanes, pentachloroethanes andhexachloroethanes; high boiling ethers, such as ethylene glycol andpropylene glycols; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); amides,such as acetamide, dimethylacetamide, dimethylformamide (DMF) orN-Methyl pyrrolidone (NMP); sulfoxides, such as dimethyl sulfoxide(DMSO); or mixtures of the said solvents. Preferred are amides,especially dimethylformamide (DMF).

Preferably, the reaction is carried out in the presence of a base.Suitable bases are known in the art. Preferred bases are organic basesand especially inorganic bases. Examples for inorganic bases arealkaline or alkaline-earth hydroxides, alkaline or alkaline-earthcarbonates and alkaline or alkaline-earth bicarbonates or other salts ofa weak acid and alkaline or alkaline-earth metals, preferably ofpotassium, sodium, calcium or cesium. Preferred inorganic bases areK₂CO₃, Na₂CO₃, MgCO₃, CaCO₃, NaOH and KOH, especially preferred isK₂CO₃. Examples for organic bases are triethyl amine, diisopropyl ethylamine (DIPEA), dimethyl aniline, pyridine or chinoline. If an organicbase is used, it is advantageous in general to use a base with a boilingpoint that is higher than the highest reaction temperature employedduring the reaction.

Alternatively, if the compound of formula IV is a compound according toformula IVb,

it can be readily obtained in an advantageous manner by reacting acompound of formula VIIb,

wherein R⁹ and q are as defined above/below and wherein L⁹ is selectedindependently from the meanings given for L¹. Preferably, L⁹ is halogen.More preferred, L⁹ is selected from the group consisting of Cl, Br andI. Especially preferred, L⁹ is Cl.with a compound of formula VIIIb,L¹⁰-X—Ar²-(R¹⁰)_(r)  VIIIbwherein L¹⁰ is H or a metal ion, preferably a metal ion, more preferreda metal ion selected from the group consisting of alkaline metal ions,alkaline-earth metal ions and aluminium ions, especially preferredalkaline metal ions, of which Li, Na and K are especially preferred; andAr², R¹⁰, r and X are as defined above/below, and especially wherein Xis (CHR¹¹)_(h)-Q-(CHR¹²)_(l), CH═N—O, CH═N—NR¹⁷, SO₂NR¹⁷, wherein R¹⁷,R¹⁸ and R¹⁹ are as defined above/below;optionally isolating the reaction product,and transferring the obtained reaction product of formula IXb

into a compound of formula Iva, preferably by hydrogenating theNO₂-moiety of the compound of formula IX into a NH₂-moiety. Methods andreaction conditions for hydrogenating said NO₂-moiety into a NH₂-moietyare known in the art. In general, it is advantageous to carry out thehydrogenation reaction in a hydrogen atmosphere in the presence of asuitable catalyst, preferably a Palladium catalyst, for example Pd/C. Ingeneral, such hydrogenation reactions are carried out in a suitablesolvent.

Suitable solvents for hydrogenation reactions are carried out in asuitable solvent. Suitable solvents for hydrogenation reactions areknown in the art. Suitable solvents, for example, are alcohols,especially methanol and ethanol, ethers, especially THF, and mixturesthereof. In general, the hydrogenation reactions are carried out atabout normal pressure or slightly elevated pressure, for example betweennormal pressure or slightly elevated pressure, for example betweennormal pressure and 3 bar pressure (about 300 kPa). The hydrogenationreaction is usually carried out in the temperature range between −20°and 150°, preferably 0° and 50°.

Ar² is preferably pyridinyl. Accordingly, the compound of formula VIIIbis preferably selected from the group consisting of formulae VIIIe andVIIIf,

wherein L¹⁰, X, R¹⁰ and r are as defined above, and especially preferredfrom the group consisting of formulae VIIIg and VIIIh,

wherein R¹⁰ and r are as defined above, and wherein M is an alkalinemetal ion and especially sodium or potassium, or the correspondingalcohols thereof.

Accordingly, in formulae IVb, VIIIb, VIIIe, VIIIf and IXb, the bridginggroup X is preferably O, S, OCH₂ and OCH₂CH₂ and especially is O.

In general, this alternative reaction is advantageous to producecompounds of formula IVbb,

wherein R⁹, q, X, Ar², R¹⁰ and r are as defined above/below.

To obtain compounds of formula IVbb, it is reasonable to employ acompound of formula VIIb that is selected from the compounds of formulaVIIbb,

wherein hal is as defined above/below and especially is Cl, and proceedthe alternative reaction as described above/below.

Accordingly, by starting from a compound a formula VIIbb and a compoundof formula VIIe, the reaction preferably leads to compounds of formulaIVbbe,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIbb and a compoundof formula VIIIf, the reaction preferably leads to compounds of formulaIVbbf,

wherein R⁹, q, X, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIbb and a compoundof formula VIIIg, the reaction preferably leads to compounds of formulaIVbbg,

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Accordingly, by starting from a compound of formula VIIb and a compoundof formula VIIIh, the reaction preferably leads to compounds of formulaIVbbh,

wherein R⁹, q, R¹⁰ and r are as defined above/below.

Some of the starting materials of the formula VIIb and/or the formulaVIIIb are known and preferably commercially available. If they are notknown, they can be prepared by methods known per se.

The reaction between the compound of formula VIIb and VIIIb ispreferably carried out in the temperature range between 0° and 250°,more preferred 50° and 220°, for example at about 90°, at about 120°, atabout 160°, at about 180° or at about 200°. Reaction times depend on therespective reactants and the respective reaction temperature, butgenerally lie in the range between 10 min and 24 hrs, preferably 30 minand 12 hrs, more preferably 1 h and 6 hrs for example about 1.5 hrs,about 3 hrs, about 4 hrs or about 5 hrs.

The reaction can be carried out in the absence or the presence of asolvent, preferable a solvent that is inert under the respectivereaction conditions. Suitable inert solvents for carrying out thereaction are known in the art. Examples for suitable solvents arealipathic hydrocarbons, aromatic carbons, for example toluene andxylenes, chlorinated hydrocarbons, such as dichlormethane,trichloromethane trichloroethylene, tetrachloroethanes,pentachloroethanes and hexachloroethanes; ethers, such as diethylether,tert.-butyl methyl ether, ethylene glycol and propylene glycols; glycolethers, such as ethylene glycol monomethyl or monoethyl ether orethylene glycol dimethyl ether (diglyme); nitriles, such asacetonitrile, amides such as acetamide, dimethylformamide (DMF) orN-methyl pyrrolidone (NMP); sulfoxides, such as dimethyl sulfoxide(DMSO); or mixtures of the said solvents.

Preferably, the reaction is carried out in the presence of a catalyst.Suitable catalysts are known in the art. Preferred catalytic activemetals and especially copper.

Preferably, the reaction is carried out by heating up a reaction mixturecomprising one compound of formula VIIb and one compound of formulaVIIIb to a suitable reaction temperature, which preferably lies at theupper end of the given temperature ranges and more preferred is in therange between 150° and 200°, for example at about 180°, preferably inthe presence of the suitable catalyst and especially in the presence ofcopper. Reaction times at this temperature are preferably as given aboveand especially in the range between 1 h and 5 hrs, for example about 3hrs. Preferably, the reaction mixture is then allowed to cool down to atemperature in the lower range of the given temperature, more preferredto a temperature in the range between 50° and 150°, for example to about90°. Preferably, a suitable solvent, especially tert.-butyl methylether, is then added and the reaction mixture is preferably kept atabout the same temperature for some more time, preferably for 30 min to2 hrs and more preferred for about one hour.

If the compound IV is a compound according to formula IVc,

it can be readily obtained in an advantageous manner by reacting acompound of formula XI

wherein L⁹ is H or a metal ion, preferably a metal ion selected from thegroup consisting of alkaline metal ions, alkaline-earth metal ions andaluminium ions, especially preferred alkaline metal ions, of which Li,Na and K are especially preferred, and even more preferred is H; and R⁹,q and X are as defined above/below, and especially wherein X is(CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein R¹¹, h and R¹² are definedabove/below, i is 0 and Q is selected from a group consisting of O, S,N—R¹⁷, (CHR¹⁸—O)_(j), (CHR¹⁸CHR¹⁹—O)_(j), CH═N—O, CH═N—NR¹⁷, SO₂NR¹⁷,wherein R¹⁷, R¹⁸ and R¹⁹ are as defined above/below;with a compound of formula XII,

wherein hal is independently select selected from the group consistingof Cl, Br and I, the residue R¹⁰ are the same or different and have themeanings given above/below and preferably have both the same meaning,and the indices r are the same or different and have the meanings givenabove/below and preferably are the same,optionally isolating the reaction product, and transferring the obtainedreaction product of formula XIII

into a compound of formula IVc, preferably by hydrogenating theNO₂-moiety of the compound of formula XIII into a NH₂-moiety, forexample as described above for the compound of formula IX.

In the compounds IVc, XII and XIII, r is preferably in each caseidentical and even more preferred in each case 0.

In formulae IVc, XI and XIII, the bridging group X is preferably O, S,OCH₂ and OCH₂CH₂ and especially is O.

In the formula XI, L⁹ is preferably H or selected from the groupconsisting of Na and K and especially preferred is H.

The reaction between the compound of formula XI and XII is preferablycarried out in the temperature range between 0° and 250°, more preferredroom temperature and 200°, for example at about 120°, at about 150° orat about 180°. Reaction times depend on the respective reactants and therespective reaction temperature, but generally lie in the range between30 min and 24 hrs, preferably one hour and 12 hrs, for example about 2hrs, about 3 hrs or about 6 hrs. The reaction can be carried out in theabsence of solvent or in the presence of an solvent, preferable asolvent that is inert under the respective reaction conditions. Suitableinert solvents for carrying out the reaction are known in the art.

Some of the starting materials of the formula XI and/or the formula XIIare known and preferably commercially available. If they are not known,they can be prepared by methods known per se.

Independently of the choosen reaction route, it is in many casespossible or even feasible to introduce residues R⁸, R⁹ and/or R¹⁰ intoone or more of the compounds described above, or, if the compoundalready comprises one or more residues R⁸, R⁹ and/or R¹⁰, to introduceadditional residues R⁸, R⁹ and/or R¹⁰ into said compound. Theintroduction of additional residues can be readily performed by methodsknown in the art and especially by aromatic substitution, for examplenucleophilic aromatic substitution or electrophilic aromaticsubstitution. For example, in compounds comprising Ar¹, wherein Ar¹comprises one or more halogen and preferably fluorine substituents, oneor more of the halogen/fluorine substituents can be easily substitutedby hydroxy, thio and/or amino substituted hydrocarbons, preferablyselected from the group consisting of HO(CH₂)_(n)NR¹¹R¹²,HO(CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², HO(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹²,HO(CH₂)_(n)NR¹¹(CH₂)_(k)NR¹¹R¹², HO(CH₂)_(n)COOR¹³,HO(CH₂)_(n)S(O)_(u)R¹³ HNR¹¹(CH₂)_(n)NR¹¹R¹²,HNR¹¹(CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², HNR¹¹(CH₂)_(n)NR¹¹(CH₂)_(k)OR¹²,HNR¹¹(CH₂)_(n)NR¹¹(CH₂)_(k)NR¹¹R¹², HNR¹¹(CH₂)_(n)COOR¹³ andHNR¹¹(CH₂)_(n)S(O)_(u)R¹³ wherein R¹¹, R¹² and R¹³ are defined as aboveand n is as defined above, preferably n is 0, 1 or 2 and especially is0, k is 1 to 4 and preferably 1 or 2, and u is preferably 2. In thisembodiment R¹¹, R¹² and R¹³ are more preferably selected independentlyfrom each other from the group consisting of H, methyl and ethyl. Evenmore preferred, the hydroxy, thio and/or amino substituted hydrocarbonsare selected from the group consisting of NH₃, HN(CH₃)₂, NH₂CH₃,HN(C₂H₅)₂, H₂NCH₂CH₂NH₂, HOCH₂CH₂NH₂, HOCH₂CH₂NHCH₃, HN(CH₃)CH₂CH₂NH₂, HN(CH₃)CH₂CH₂N(CH₃)₂, H N(CH₃)CH₂CH₂N(CH₃)₂, HN(CH₃)CH₂CH₂OCH₃,HOCH₂CH₂N(CH₃)₂, HOCH₂CH₂N(CH₂CH₃)₂, HSCH₃, HSC₂H₅, and compounds of theformulae

and/or compounds of formulae

and/or protected derivatives thereof, preferably partially protectedderivatives therof, and salts and especially metal salts thereof. Inthis respect, protected derivatives thereof, preferably partiallyprotected derivatives therof, wherein one, two or more, prefrably one ortwo, of the hydrogen atoms of the free amino and/or hydroxy groups (i.e.NH, NH₂ and/or OH groups) are replaced by amino protecting groups orhydroxy protecting groups, respectively. Such protecting groups andmethods for the preparation of protected or partially protectedderivatives and the removal of the protcting groups after theirintroduction into the compounds according to the invention are known inthe art.

On the other hand, it is in many cases possible or even feasible tomodify or derivatize one or more of the residue is R⁸, R⁹ and R¹⁰ intoresidues R⁸, R⁹ and/or R¹⁰ other than the ones originally present. Forexample, CH₃groups can be oxidised into aldehyde groups or carbonic acidgroups, thio atom containing groups, for example S-alkyl or S-arylgroups, can be oxidised into SO₂-alkyl or SO₂-aryl groups, respectively,carbonic acid groups can be derivatized to carbonic acid ester groups orcarbon amide groups and carbonic acid ester groups or carbon amidegroups can be hydrolysed into the corresponding carbonic acid groups.Methods for performing such modifications or derivatizations are knownin the art, for example from Houben-Weyl, Methods of Organic Chemistry.

Every reaction step described herein can optionally be followed by oneor more working up procedures and/or isolating procedures. Suitable suchprocedures are known in the art, for example from standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Examples for suchprocedures include, but are not limited to evaporating a solvent,distilling, crystallization, fractionised crystallization, extractionprocedures, washing procedures, digesting procedures, filtrationprocedures, chromatography, chromatography by HPLC and dryingprocedures, especially drying procedures in vacuo and/or elevatedtemperature.

A base of the formula I or the formula II can be converted into theassociated acid-addition salt using an acid, for example by reaction ofequivalent amounts of the base and the acid in a preferably inertsolvent, such as ethanol, followed by evaporation. Suitable acids forthis reaction are, in particular, those which give physiologicallyacceptable salts. Thus, it is possible to use inorganic acids, forexample sulfuric acid, sulfurous acid, dithionic acid, nitric acid,hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as, for example, orthophosphoric acid, sulfamicacid, furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, hexanoic acid, octanoic acid, decanoic acid,hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid,malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylicacid, p-toluene-sulfonic acid, glycolic acid, embonic acid,chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline,glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid,cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and-disulfonic acids or laurylsulfuric acid. Salts with physiologicallyunacceptable acids, for example picrates, can be used to isolate and/orpurify the compounds of the formula I. On the other hand, compounds ofthe formula I can be converted into the corresponding metal salts, inparticular alkali metal salts or alkaline earth metal salts, or into thecorresponding ammonium salts, using bases (for example sodium hydroxide,potassium hydroxide, sodium carbonate or potassium carbonate). Suitablesalts are furthermore substituted ammonium salts, for example thedimethyl-, diethyl- and diisopropyl-ammonium salts, monoethanol-,diethanol- and diisopropanolammonium salts, cyclohexyl- anddicyclohexylammonium salts, dibenzylethylenediammonium salts,furthermore, for example, salts with arginine or lysine.

On the other hand, if desired, the free bases of the formula I or theformula II can be liberated from their salts using bases (for examplesodium hydroxide, potassium hydroxide, sodium carbonate or potassiumcarbonate).

The invention relates to compounds of the formula I and of the formulaII and physiologically acceptable salts and solvates thereof asmedicaments.

The invention also relates to the compounds for the formula I and of theformula II and physiologically acceptable salts and solvates thereof askinase inhibitors.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically acceptable salts and/or solvatesthereof for the preparation of pharmaceutical compositions and/orpharmaceutical preparations, in particular by non-chemical methods. Theinvention furthermore relates to the use of the compounds of the formulaII and/or physiologically acceptable salts and/or solvates thereof forthe preparation of pharmaceutical compositions and/or pharmaceuticalpreparations, in particular by non-chemical methods. In this cases, oneor more compounds according to the invention can be converted into asuitable dosage form together with at least one solid, liquid and/orsemi-liquid excipient or adjuvant and, if desired, in combination withone or more further active ingredients.

The invention further relates to the use of one or more of the compoundsaccording to the invention, selected from the group consisting ofcompounds of the formula I as free bases, solvates of compounds of theformula I, salts of compounds of formula I, of compounds of the formulaII as free bases, solvates of compounds of the formula II and salts ofcompounds of formula II, for the production of pharmaceuticalcompositions and/or pharmaceutical preparations, in particular by anon-chemical route. In general, non-chemical routes for the productionof pharmaceutical compositions and/or pharmaceutical preparationscomprise processing steps on suitable mechanical means known in the artthat transfer one or more compounds according to the invention into adosage form suitable for administration to a patient in need of such atreatment. Usually, the transfer of one or more compounds according tothe invention into such a dosage form comprises the addition of one ormore compounds, selected from the group consisting of carriers,excipients, auxiliaries and pharmaceutical active ingredients other thanthe compounds according to the invention. Suitable processing stepsinclude, but are not limited to combining, milling, mixing, granulating,dissolving, dispersing, homogenizing, casting and/or compressing therespective active and non-active ingridients. In this respect, activeingredients are preferably at least one compound according to thisinvention and one or more additional compounds other than the compoundsaccording to the invention, which show valuable pharmaceuticalproperties, preferably those pharmaceutical active agents other than thecompounds according to invention which are disclosed herein.

The process for preparing pharmaceutical compositions and/orpharmaceutical preparations preferably comprises one or more processingsteps, selected from the group consisting of combining, milling, mixing,granulating, dissolving, dispersing, homogenizing and compressing. Theone or more processing steps are preferably performed on one or more ofthe ingredients which are to form the pharmaceutical composition and/orpharmaceutical preparation preferably according to invention. Even morepreferred, said processing steps are performed on two or more of theingredients which are to form the pharmaceutical composition and/orpharmaceutical preparation, said ingredients comprising one or morecompounds according to the invention and, additionally, one or morecompounds, preferably selected from the group consisting of activeingredients other than the compounds according to the invention,excipients, auxiliaries, adjuvants and carriers. Mechanical means forperforming said processing steps are known in the art, for example fromUllmann's Encyclopedia of Industrial Chemistry, 5th Edition.

Preferably, one or more compounds according to the invention areconverted into a suitable dosage form together with at least onecompound selected from the group consisting of excipients, auxiliaries,adjuvants and carriers, especially solid, liquid and/or semi-liquidexcipients, auxiliaries, adjuvants and carriers, and, if desired, incombination with one or more further active ingredients.

Suitable dosage forms include, but are not limited to tablets, capsules,semi-solids, suppositories, aerosols, which can be produced according tomethods known in the art, for example as described below:

-   tablets mixing of active ingredient/s and auxiliaries, compression    of said mixture into tablets (direct compression), optionally    granulation of part of mixture before compression-   capsules mixing of active ingredient/s and auxiliaries to obtain a    flowable powder, optionally granulating powder, filling    powders/granulate into opened capsules, capping of capsules-   semi-solids (ointments, gels, creams) dissolving/dispersing active    ingredient/s in an aqueous or fatty carrier; subsequent mixing of    aqueous/fatty phase with complementary fatty resp. aqueous phase,    homogenisation (creams only)-   suppositories (rectal and vaginal) dissolving/dispersing active    ingredient/s in carrier material liquified by heat (rectal: carrier    material normally a wax; vaginal: carrier normally a heated solution    of a gelling agent), casting said mixture into suppository forms,    annealing and withdrawal suppositories from the forms-   aerosols: dispersing/dissolving active agent/s in a propellant,    bottling said mixture into an atomizer

The invention thus relates to pharmaceutical compositions and/orpharmaceutical preparations comprising at least one compound of theformula I and/or one of its physiologically acceptable salts and/orsolvates and especially to pharmaceutical compositions and/orpharmaceutical preparations comprising at least one compound of theformula II and/or one of its physiologically acceptable salts and/orsolvates.

Preferably, the pharmaceutical compositions and/or pharmaceuticalpreparations according to the invention contain a therapeutic effectiveamount of one or more compounds according to the invention. Saidtherapeutic effective amount of one or more of the compounds accordingto the invention is known to the skilled artisan or can be easilydetermined by standard methods known in the art. For example, thecompounds according to the invention can be administered to a patient inan analogous manner to other compounds that are effective as raf-kinaseinhibitors, especially in an analogous manner to the compounds describedin WO 00/42012 (Bayer). Usually, suitable doses that are therapeuticallyeffective lie in the range between 0.0005 mg and 1000 mg, preferablybetween 0.005 mg and 500 mg and especially between 0.5 and 100 mg perdose unit. The daily dose comprises preferably more than 0.001 mg, morepreferred more than 0.01 milligram, even more preferred more than 0.1 mgand especially more than 1.0 mg, for example more than 2.0 mg, more than5 mg, more than 10 mg, more than 20 mg, more than 50 mg or more than 100mg, and preferably less than 1500 mg, more preferred less than 750 mg,even more preferred less than 500 mg, for example less than 400 mg, lessthan 250 mg, less than 150 mg, less than 100 mg, less than 50 mg or lessthan 10 mg.

The specific dose for the individual patient depends, however, on themultitude of factors, for example on the efficacy of the specificcompounds employed, on the age, body weight, general state of health,the sex, the kind of diet, on the time and route of administration, onthe excretion rate, the kind of administration and the dosage form to beadministered, the pharmaceutical combination and severity of theparticular disorder to which the therapy relates. The specifictherapeutic effective dose for the individual patient can readily bedetermined by routine experimentation, for example by the doctor orphysician which advises or attends the therapeutic treatment.

However, the specific dose for each patient depends on a wide variety offactors, for example on the efficacy of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and method of administration, on the rate of excretion,medicament combination and severity of the particular illness to whichthe therapy applies. Parenteral administration is preferred. Oraladministration is especially preferred.

These compositions and/or preparations can be used as medicaments inhuman or veterinary medicine. Suitable excipients are organic orinorganic substances which are suitable for enteral (for example oral),parenteral or topical administration and do not react with the novelcompounds, for example water, vegetable oils, benzyl alcohols, alkyleneglycols, polyethylene glycols, glycerol triacetate, gelatine,carbohydrates, such as lactose or starch, magnesium stearate, talc orvaseline. Examples for suitable dosage forms, which are especiallysuitable for oral administration are, in particular, tablets, pills,coated tablets, capsulees, powders, granules, syrups, juices or drops.Further examples for suitable dosage forms, which are especiallysuitable for rectal administration are suppositories, further examplesfor suitable dosage forms, which are especially suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders. The novel compounds mayalso be lyophilised and the resultant lyophilisates used, for example,for the preparation of injection preparations. The compositions and/orpreparations indicated may be sterilized and/or comprise assistants,such as lubricants, preservatives, stabilizers and/or wetting agents,emulsifiers, salts for modifying the osmotic pressure, buffersubstances, dyes and flavors and/or one or more further activeingredients, for example one or more vitamins.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronized form, in which case one or more additional physiologicallyacceptable solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

The compounds of the formula I and their physiologically acceptablesalts and solvates and especially the compounds of formula II and theirphysiologically acceptable salts and solvates can be employed forcombating one or more diseases, for example allergic diseases, psoriasisand other skin diseases, especially melanoma, autoimmune diseases, suchas, for example, rheumatoid arthritis, multiple sclerosis, Crohn'sdisease, diabetes mellitus or ulcerative colitis.

In general, the substances according to the invention are preferablyadministered in doses corresponding to the compound rolipram of between1 and 500 mg, in particular between 5 and 100 mg per dosage unit. Thedaily dose is preferably between about 0.02 and 10 mg/kg of body weight.However, the specific dose for each patient depends on a wide variety offactors, for example on the efficacy of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and method of administration, on the excretion rate, medicamentcombination and severity of the particular illness to which the therapyapplies.

The compounds of the formula I according to claim 1 and/or theirphysiologically acceptable salts are also used in pathological processeswhich are maintained or propagated by angiogenesis, in particular intumours, restenoses, diabetic retinopathy, macular degenerative diseaseor rheumatoid arthritis.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

For use in the subject methods, the subject compounds may be formulatedwith pharmaceutically active agents other than the compounds accordingto the invention, particularly other anti-metastatic, antitumor oranti-angiogenic agents. Angiostatic compounds of interest includeangiostatin, enclostatin, carboxy terminal peptides of collagen alpha(XV), etc. Cytotoxic and cytostatic agents of interest includeadriamycin, aleran, Ara-C, BICNU, busulfan, CNNU, cisplatinum, cytoxan,daunorubicin, DTIC, 5-FU, hydrea, ifosfamicle, methotrexate,mithramycin, mitomycin, mitoxantrone, nitrogen mustard, velban,vincristine, vinblastine, VP-16, carboplatinum, fludarabine,gemcitabine, idarubicin, irinotecan, leustatin, navelbine, taxol,taxotere, topotecan, etc.

The compounds of the invention have been shown to have antiproliferativeeffects in an in vivo xenograft tumor model. The subject compounds areadministered to a subject having a hyperproliferative disorders, e.g.,to inhibit tumor growth, to decrease inflammation associated with alymphoproliferative disorder, to inhibit graft rejection, orneurological damage due to tissue repair, etc. The present compounds areuseful for prophylactic or therapeutic purposes. As used herein, theterm “treating” is used to refer to both prevention of disease, andtreatment of pre-existing conditions. The prevention of proliferation isaccomplished by administration of the subject compounds prior todevelopment of overt disease, e.g., to prevent the regrowth of tumors,prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively the compounds are used totreat ongoing disease, by stabilizing or improving the clinical symptomsof the patient.

The host, or patient, may be from any mammalian species, e.g., primatesp., particularly human; rodents, including mice, rats and hamsters;rabbits; equines, bovines, canines, felines; etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the subjectcompounds may be determined by in vitro testing. Typically a culture ofthe cell is combined with a subject compound at varying concentrationsfor a period of time sufficient to allow the active agents to inducecell death or inhibit migration, usually between about one hour and oneweek. For in vitro testing, cultured cells from a biopsy sample may beused. The viable cells left after treatment are then counted.

The dose will vary depending on the specific compound utilized, specificdisorder, patient status, etc. Typically a therapeutic dose will besufficient to substantially decrease the undesirable cell population inthe targeted tissue, while maintaining patient viability. Treatment willgenerally be continued until there is a substantial reduction, e.g., atleast about 50%, decrease in the cell burden, and may be continued untilthere are essentially none of the undesirable cells detected in thebody.

The compounds according to the invention are preferably administered tohuman or nonhuman animals, more preferred to mammalian animals andespecially to humans.

The compounds also find use in the specific inhibition of a signalingpathway mediated by protein kinases. Protein kinases are involved insignaling pathways for such important cellular activities as responsesto extracellular signals and cell cycle checkpoints. Inhibition ofspecific protein kinases provided a means of intervening in thesesignaling pathways, for example to block the effect of an extracellularsignal, to release a cell from cell cycle checkpoint, etc. Defects inthe activity of protein kinases are associated with a variety ofpathological or clinical conditions, where there is a defect in thesignaling mediated by protein kinases. Such conditions include thoseassociated with defects in cell cycle regulation or in response toextracellular signals, e.g., immunological disorders, autoimmune andimmunodeficiency diseases; hyperproliferative disorders, which mayinclude psoriasis, arthritis, inflammation, endometriosis, scarring,cancer, etc. The compounds of the present invention are active ininhibiting purified kinase proteins preferably raf kinases, e.g., thereis a decrease in the phosphorylation of a specific substrate in thepresence of the compound. The compounds of the invention may also beuseful as reagents for studying signal transduction or any of theclinical disorders listed throughout this application.

There are many disorders associated with a dysregulation of cellularproliferation. The conditions of interest include, but are not limitedto, the following conditions. The subject compounds are useful in thetreatment of a variety of conditions where there is proliferation and/ormigration of smooth muscle cells, and/or inflammatory cells into theintimal layer of a vessel, resulting in restricted blood flow throughthat vessel, e.g., neointimal occlusive lesions. Occlusive vascularconditions of interest include atherosclerosis, graft coronary vasculardisease after transplantation, vein graft stenosis, peri-anastomaticprothetic graft stenosis, restenosis after angioplasty or stentplacement, and the like.

Diseases where there is hyperproliferation and tissue remodelling orrepair or reproductive tissue, e.g., uterine, testicular and ovariancarcinomas, endometriosis, squamous and glandular epithelial carcinomasof the cervix, etc. are reduced in cell number by administration of thesubject compounds. The growth and proliferation of neural cells is alsoof interest.

Tumor cells are characterized by uncontrolled growth, invasion tosurrounding tissues, and metastatic spread to distant sites. Growth andexpansion requires an ability not only to proliferate, but also todown-modulate cell death (apoptosis) and activate angiogenesis toproduce a tumor neovasculature.

Tumors of interest for treatment include carcinomas, e.g., colon,duodenal, prostate, breast, melanoma, ductal, hepatic, pancreatic,renal, endometrial, stomach, dysplastic oral mucosa, polyposis, invasiveoral cancer, non-small cell lung carcinoma, transitional and squamouscell urinary carcinoma etc.; neurological malignancies; e.g.neuroplastoma, gliomas, etc.; hematological malignancies, e.g.,childhood acute leukaemia, non-Hodgkin's lymphomas, chronic lymphocyticleukaemia, malignant cutaneous T-cells, mycosis fungoides, non-MFcutaneous T-cell-lymphoma, lymphomatoid papulosis, T-cell rich cutaneouslymphoid hyperplasia, bullous pemphigoid, discoid lupus erythematosus,lichen planus, etc.; and the like.

Tumors of neural tissue are of particular interest, e.g., gliomas,neuromas, etc. Some cancers of particular interest include breastcancers, which are primarily adenocarcinoma subtypes. Ductal carcinomain situ is the most common type of noninvasive breast cancer. In DCIS,the malignant cells have not metastasized through the walls of the ductsinto the fatty tissue of the breast. Infiltration (or invasive) ductalcarcinoma (IDC) has metastasized through the wall of the duct andinvaded the fatty tissue of the breast. Infiltrating (or invasive)lobular carcinoma (ILC) is similar to IDC, in that it has the potentialto metastasize elsewhere in the body.

About 10% to 15% of invasive breast cancers are invasive lobularcarcinomas. Also of interest is non-small cell lung carcinoma. Non-smallcell lung cancer (NSCLC) is made up of three general subtypes of lungcancer. Epidermoid carcinoma (also called squamos cell carcinoma)usually starts in one of the larger bronchial tubes and grows relativelyslowly. The size of these tumors can range from very small to quitelarge. Adenocarcinoma starts growing near the outside surface of thelung and may vary in both size and growth rate. Some slowly growingadenocarcinomas are described as alveolar cell cancer. Large cellcarcinoma starts near the surface of the lung, grows rapidly, and thegrowth is usually fairly large when diagnosed. Other less common formsof lung cancer are carcinoid, cylindroma, mucoepidermoid, and malignantmesothelioma.

Melanoma is a malignant tumor of melanocytes. Although most melanomasarise in the skin, they also may arise from mucosal surfaces or at othersites to which neural crest cells migrate. Melanoma occurs predominantlyin adults, and more than half of the cases arise in apparently normalareas of the skin. Prognosis is affected by clinical and histologicalfactors and by anatomic location of the lesion. Thickness and/or levelof invasion of the melanoma, mitotic index, tumor infiltratinglymphocytes, and ulceration or bleeding at the primary site affect theprognosis. Clinical staging is based on whether the tumor has spread toregional lymph nodes or distant sites. For disease clinically confinedto the primary site, the greater the thickness and depth of localinvasion of the melanoma, the higher the chance of lymph node metastasesand the worse the prognosis. Melanoma can spread by local extension(through lymphatics) and/or by hematogenous routes to distant sites. Anyorgan may be involved by metastases, but lungs and liver are commonsites.

Other hyperproliferative diseases of interest relate to epidermalhyperproliferation, tissue, remodeling and repair. For example, thechronic skin inflammation of psoriasis is associated with hyperplasticepidermal keratinocyctes as well as infiltrating mononuclear cells,including CD4+ memory T cells, neutrophils and macrophages.

The proliferation of immune cells is associated with a number ofautoimmune and lymphoproliferative disorders. Diseases of interestinclude multiple sclerosis, rheumatoid arthritis and insulin dependentdiabetes mellitus. Evidence suggests that abnormalities in apoptosisplay a part in the pathogenesis of systemic lupus erythematosus (SLE).Other lymphoproliferative conditions the inherited disorder oflymphocyte apoptosis, which is an autoimmune lymphoproliferativesyndrome, as well as a number of leukemia's and lymphomas. Symptoms ofallergies to environmental and food agents, as well as inflammatorybowel disease, may also be alleviated by the compounds of the invention.

Surprisingly, it has been found that oxamide derivatives according toinvention are able to interact with signaling pathways, especially thesignaling pathways described herein and preferably the raf-kinasesignaling pathway. Oxamide derivatives according to the inventionpreferably show advantagous biological activity which is easilydemonstrated in enzyme based assays, for example assays as describedherein. In such enzyme based assays, oxamide derivatives according toinvention show and effect, preferably an inhibiting effect which isusually documented by IC₅₀ values in a suitable range, preferably in themicromolar range and more preferred in the nanomolar range.

In general, compounds according to the invention are to be regarded assuitable kinase-modulators and especially suitable kinase-inhibitorsaccording to the invention if they show an effect or an activity to oneor more kinases, preferably to one or more raf-kinases that preferablylies, determined as IC₅₀-value, in the range of 100 μmol or below,preferably 10 μmol or below, more preferably in the range of 3 μmol orbelow, even more preferably in the range of 1 μmol or below and mostpreferably in the nanomolar range. Especially preferred for useaccording to the invention are kinase-inhibitors as defined above/below,that show an activity, determined as IC₅₀-value, to one or moreraf-kinases, preferably including A-raf, B-raf and c-raf1 or consistingof A-raf, B-raf and c-raf1 and more preferred including c-raf1 orconsisting of c-raf1, in the range of 0.5 μmol or below and especiallyin the range of 0.1 μmol or below. In many cases an IC₅₀-value at thelower end of the given ranges is advantageous and in some cases it ishighly desirable that the IC₅₀-value is as small as possible or the heIC₅₀-values are as small as possible, but in general IC₅₀-values thatlie between the above given upper limits and a lower limit in the rangeof 0.0001 μmol, 0.001 μmol, 0.01 μmol or even above 0.1 μmol aresufficient to indicate the desired pharmaceutical activity. However, theactivities measured can vary depending on the respective testing systemor assay chosen.

Alternatively, the advantageous biological activity of the compoundsaccording to the invention can easily be demonstrated in in vitroassays, such as in vitro proliferation assays or in vitro growth assays.Suitable in vitro assays are known in the art, for example from theliterature cited herein and the references cited in the literature orcan be performed as described below, or can be developed and/orperformed in an analogous manner thereof.

As an example for an in vitro growth assay, human tumor cell lines, forexample HCT116, DLD-1 or MiaPaCa, containing mutated K-ras genes can beused in standard proliferation assays, for example for anchoragedependent growth on plastic or anchorage independent growth in softagar. Human tumor cell lines are commercially available, for examplefrom ATCC (Rockville Md.), and can be cultured according to methodsknown in the art, for example in RPMI with 10% heat inactivated fetalbovine serum and 200 mM glutamine. Cell culture media, fetal bovineserum and additives are commercially available, for example fromInvitrogen/Gibco/BRL (Karlsruhe, Germany) and/or QRH Biosciences(Lenexa, Kans.). In a standard proliferation assay for anchoragedependent growth, 3×10³ cells can be seeded into 96-well tissue cultureplates and allowed to attach, for example overnight at 37° C. in a 5%CO₂ incubator. Compounds can be titrated in media in dilution series andadded to 96 well cell cultures. Cells are allowed to grow, for examplefor 1 to 5 days, typically with a feeding of fresh compound containingmedia at about half of the time of the growing period, for example onday 3, if the cells are allowed to grow 5 days. Proliferation can bemonitored by methods known in the art, such as measuring metabolicactivity, for example with standard XTT calorimetric assay (BoehringerMannheim) measured by standard ELISA plate reader at OD 490/560, bymeasuring ³H-thymidine incorporation into DNA following an 8 h culturewith 1 μCu ³H-thymidine, harvesting the cells onto glass fiber matsusing a cell harvester and measuring ³H-thymidine incorporation byliquid scintillation counting, or by staining techniques, such ascrystal violet staining. Other suitable cellular assay systems are knownin the art.

Alternatively, for anchorage independent cell growth, cells can beplated at 1×10³ to 3×10³ in 0.4% Seaplaque agarose in RPMI completemedia, overlaying a bottom layer containing only 0.64% agar in RPMIcomplete media, for example in 24-well tissue culture plates. Completemedia plus dilution series of compounds can be added to wells andincubated, for example at 37° C. in a 5% CO₂ incubator for a sufficienttime, for example 10-14 days, preferably with repeated feedings of freshmedia containing compound, typically at 3-4 day intervals. Colonyformation and total cell mass can be monitored, average colony size andnumber of colonies can be quantitated according to methods known in theart, for example using image capture technology and image analysissoftware. Image capture technology and image analysis software, such asImage Pro Plus or media Cybernetics.

As discussed herein, these signaling pathways are relevant for variousdisorders. Accordingly, by interacting with one or more of saidsignaling pathways, oxamide derivatives are useful in the preventionand/or the treatment of disorders that are dependent from said signalingpathways.

The compounds according to the invention are preferably kinasemodulators and more preferably kinase inhibitors. According to theinvention, kinases include, but are not limited to one or moreRaf-kinases, one or more Tie-kinases, one or more VEGFR-kinases, one ormore PDGFR-kinases, p38-kinase and/or SAPK2alpha.

Raf-kinases in this respect preferably include or consist of A-Raf,B-Raf and c-Raf1.

Tie-kinases in this respect preferably include or consist of Tie-2kinase.

VEGFR-kinases in this respect preferably include or consist of VEGFR-2kinase.

Due to the kinase modulating or inhibting properties of the compoundsaccording to the invention, the compounds according to the inventionpreferably interact with one or more signalling pathways which arepreferably cell signalling pathways, preferably by downregulating orinhibiting said signaling pathways. Examples for such signallingpathways include, but are not limited to the raf-kinase pathway, theTie-kinase pathway, the VEGFR-kinase pathway, the PDGFR-kinase pathway,the p38-kinase pathway, the SAPK2alpha pathway and/or the Ras-pathway.

Modulation of the raf-kinase pathway plays an important role in variouscancerous and noncancerous disorders, preferably cancerous disorders,such as dermatological tumors, haematological tumors, sarcomas, squamouscell cancer, gastric cancer, head cancer, neck cancer, oesophagealcancer, lymphoma, ovary cancer, uterine cancer and/or prostate cancer.Modulation of the raf-kinase pathway plays a even more important role invarious cancer types which show a constitutive activation of theraf-kinase dependent signalling pathway, such as melanoma, colorectalcancer, lung cancer, brain cancer, pancreatic cancer, breast cancer,gynaecological cancer, ovarian cancar, thyroid cancer, chronic leukaemiaand acute leukaemia, bladder cancer, hepatic cancer and/or renal cancer.Modulation of the raf-kinase pathway plays also an important role ininfection diseases, preferably the infection diseases as mentionedabove/below and especially in Helicobacter pylori infections, such asHelicobacter pylori infection during peptic ulcer disease.

One or more of the signalling pathways mentioned above/below andespecially the VEGFR-kinase pathway plays an important role inangiogenesis. Accordingly, due to the kinase modulating or inhibtingproperties of the compounds according to the invention, the compoundsaccording to the invention are suitable for the prophylaxis and/ortreatment of pathological processes or disorders caused, mediated and/orpropagated by angiogenesis, for example by inducing anti-angiogenesis.Pathological processes or disorders caused, mediated and/or propagatedby angiogenesis include, but are not limited to tumors, especially solidtumors, arthritis, especially heumatic or rheumatoid arthritis, diabeticretinopathy, psoriasis, restenosis; fibrotic disorders; mesangial cellproliferative disorders, diabetic nephropathy, malignantnephrosclerosis, thrombotic microangiopathy syndromes, organ transplantrejection, glomerulopathies, metabolic disorders, inflammation andneurodegenerative diseases, and especially solid tumors, rheumaticarthritis, diabetic retinopathy and psoriasis.

Modulation of the p38-signalling pathway plays an important role invarious cancerous and although in various noncancerous disorders, suchas fibrosis, atherosclerosis, restenosis, vascular disease,cardiovascular disease, inflammation, renal disease and/or angiogenesis,and especially noncancerous disorders such as rheumatoid arthritis,inflammation, autoimmune disease, chronic obstructive pulmonary disease,asthma and/or inflammatory bowel disease.

Modulation of the PDGF-signalling pathway plays an important role invarious cancerous and although in various noncancerous disorders, suchas rheumatoid arthritis, inflammation, autoimmune disease, chronicobstructive pulmonary disease, asthma and/or inflammatory bowel disease,and especially noncancerous disorders such as fibrosis, atherosclerosis,restenosis, vascular disease, cardiovascular disease, inflammation,renal disease and/or angiogenesis.

Subject of the present invention are therefore oxamide derivativesaccording to the invention as promoters or inhibitors, preferably asinhibitors, of the signaling pathways described herein. Preferredsubject of the invention are therefore oxamide derivatives according tothe invention as promoters or inhibitors, preferably as inhibitors ofthe raf-kinase pathway. More preferred subject of the invention aretherefore oxamide derivatives according to the invention as promoters orinhibitors, preferably as inhibitors of the raf-kinase. Even morepreferred subject of the invention are oxamide derivatives according toinvention as promoters or inhibitors, preferably as inhibitors of one ormore raf-kinases, selected from the group consisting of A-raf, B-raf andc-raf1. Especially preferred subject of the invention are oxamidederivatives according to the invention as promoters or inhibitors,preferably as inhibitors of c-raf1.

Thus, subject of the present invention are oxamide derivatives accordingto the invention as medicaments. Subject of the present invention areoxamide derivatives according to the invention as medicament activeingredients. Further subject of the present invention is the use of oneor more oxamide derivatives according to the invention as apharmaceutical. Further subject of the present invention is the use ofone or more oxamide derivatives according to the invention in thetreatment and/or the prophylaxis of disorders, preferably the disordersdescribed herein, more preferred disorders that are caused, mediatedand/or propagated by signalling pathways discussed herein, even morepreferred disorders that are caused, mediated and/or propagated byraf-kinases and especially disorders that are caused, mediated and/orpropagated by raf-kinases, selected from the group consisting of A-raf,B-raf and c-raf1. Usually, the disorders discussed herein are dividedinto two groups, hyperproliferative and non hyperproliferativedisorders. In this context, psioarsis, arthritis, inflammation,endometriosis, scarring, begnin prostatic hyperplasia, immunologicaldiseases, autoimmune diseases and immunodeficiency diseases are to beregarded as noncancerous disorders, of which arthritis, inflammation,immunological diseases, autoimmune diseases and immunodeficiencydiseases are usually regarded as non hyperproliferative disorders. Inthis context, brain cancer, lung cancer, squamous cell cancer, bladdercancer, gastric cancer, pancreatic cancer, hepatic cancer, renal cancer,colorectal cancer, breast cancer, head cancer, neck cancer, oesophagealcancer, gynaecological cancer, thyroid cancer, lymphoma, chronicleukaemia and acute leukaemia are to be regarded as cancerous disorders,all of which are usually regarded as hyperproliferative disorders.Especially cancerous cell growth and especially cancerous cell growthmediated by raf-kinase is a disorder which is a target of the presentinvention. Subject of the present invention therefore are oxamidederivatives according to the invention as medicaments and/or medicamentactive ingredients in the treatment and/or the prophylaxis of saiddisorders and the use of oxamide derivatives according to the inventionfor the manufacture of a pharmaceutical for the treatment and/or theprophylaxis of said disorders as well as a method of treatment of saiddisorders, comprising administering one or more oxamide derivativesaccording to the invention to a patient in need of such anadministration. Accordingly, subject of the present invention arepharmaceutical compositions that contain one or more oxamide derivativesaccording to the invention. Subject of the present invention areespecially pharmaceutical compositions that contain one or more oxamidederivatives according to the invention and one or more additionalcompounds (other than the compounds of the instant invention),preferably selected from the group consisting of physiologicallyacceptable excipients, auxiliaries, adjuvants, carriers andpharmaceutically active ingredients other than the compounds accordingto the invention.

Accordingly, subject of the present invention is a process for themanufacture of a pharmaceutical composition, wherein one or more oxamidederivatives according to the invention and one or more compounds (otherthan the compounds of the instant invention), preferably selected fromthe group consisting of carriers, excipients, auxiliaries, adjuvants andpharmaceutically active ingredients other than the compounds accordingto the invention.

Accordingly, the use of the compounds according to the invention in thetreatment of hyperproliferative disorders is a subject of the instantinvention.

Accordingly, the use of the compounds according to the invention forproducing a medicament for the treatment of hyperproliferative disordersis a subject of the instant invention.

Above and below, all temperatures are given in ° C. In the examplesbelow, “conventional work-up” means that the organic phase is washedwith saturated NaHCO₃ solution, if desired with water and saturated NaClsolution, the phases are separated, the organic phase is dried oversodium sulfate and evaporated, and the product is purified bychromatography on silica gel, by preparative HPLC and/or bycrystallization.

The present invention relates to oxamide derivatives of formula I, theuse of the compounds of formula I as inhibitors of raf-kinase, the useof the compounds of formula I for the manufacture of a pharmaceuticalcomposition and a method of treatment, comprising administering saidpharmaceutical composition to a patient.

EXAMPLES

Synthesis of the Phenylamine Moieties

4-(4-Pyridinyloxy)phenylamine

a) 195 g (1.4 mol) of 4-nitrophenol and 445.2 g (1.4 mol) of bipyridinewere thoroughly mixed and slowly heated to 150° C. After the batch hadbeen stirred at 150° C. for 3 hours, it was poured while still hot into5 l of ice-water. The mixture was acidified using hydrochloric acid, andthe aqueous phase was washed 2× with 3 l of methyl tert-butyl ether. Theaqueous phase was rendered basic (pH 12) using conc. sodium hydroxidesolution and extracted 2× with 3 l of methyl tert-butyl ether. Thecombined organic phases were washed 4× with 1 l of water, dried usingNa₂SO₄, filtered and evaporated. The residue was dissolved in 100 ml ofether, and the product was brought to crystallization in the ice bath byaddition of 200 ml of petroleum ether. The crystals were filtered offwith suction and dried under reduced pressure.

Yield: 75 g (25%) of 1, brown crystals

b) Compound 1 was hydrogenated at room temperature using Pd/C in MeOH.The reaction solution was filtered through kieselguhr and rinsed withMeOH, and the filtrate was subsequently evaporated. The residue wasdigested with diethyl ether:petroleum ether=2:1, filtered off withsuction, rinsed with petroleum ether and dried overnight at 40° C. underreduced pressure.

Yield: 50.94 g (76%) of 2, brown crystals

3-(4-Pyridinyloxy)phenylamine

a) 200 g (1.44 mol) of 3-nitrophenol and 457.93 g (1.44 mol) ofbipyridine were thoroughly mixed and slowly heated to 150° C. After thebatch had been stirred at 150° C. for 3 hours, it was poured while stillhot into 5 l of ice-water. The mixture was acidified using hydrochloricacid, and the aqueous phase was washed 2× with 3 l of methyl tert-butylether. The aqueous phase was rendered basic (pH 12) using conc. sodiumhydroxide solution and extracted 2× with 3 l of methyl tert-butyl ether.The combined organic phases were washed 4× with 1 l of water, dried overNa₂SO₄, filtered and evaporated. The residue was dissolved in 2 l ofdiethyl ether, 20 g of activated carbon were added, and the mixture wasstirred for 1 hour and filtered. The filtrate was evaporated to about200 ml, and the product was brought to crystallization in the ice bathby addition of 500 ml of petroleum ether. The crystals were filtered offwith suction and dried under reduced pressure.

Yield: 131 g (42%) of 3, beige crystals

b) Compound 3 was hydrogenated at room temperature using Pd/C in MeOH.The reaction solution was filtered through kieselguhr and rinsed withMeOH, and the filtrate was subsequently evaporated. The residue wasdigested with diethyl ether, filtered off with suction, rinsed withdiethyl ether and dried overnight at 40° C. under reduced pressure.

Yield: 98.08 g (87%) of 4, pale-brown crystals

4-(3-Pyridinyloxy)phenylamine

125 g (0.94 mol) of 3-hydroxypyridine, potassium salt, 300 g of1-chloro-4-nitrobenzene and 15 g of copper were homogenized and heatedto 180° C. The reaction mixture was stirred at 180° C. for 6 hours andcooled to 90° C., and methyl tert-butyl ether was subsequently addedrapidly. The suspension was stirred for 1 hour and filtered withsuction. The filtrate was extracted 3× with 1 l of 10% HCl solution. Theaqueous phase was rendered alkaline using NH₄OH solution and extractedwith ethyl acetate. The combined organic phases were dried using Na₂SO₄,filtered and evaporated. The residue was purified by columnchromatography (1 kg of silica gel, eluent: dichloromethane), taken upin 10% HCl solution and extracted with ethyl acetate. The aqueous phasewas rendered alkaline using NH₄OH solution, and the deposited crystalswere filtered off with suction, washed with a little cold water anddried in air for 4 days.

Yield: 44.7 g (22%) of 5, brown crystals

b) Compound 5 was hydrogenated at room temperature using Pd/C inMeOH/THF. The reaction solution was filtered through kieselguhr andrinsed with MeOH, and the filtrate was subsequently evaporated. Theresidue was digested with diethyl ether, filtered off with suction,rinsed with diethyl ether and dried overnight at 40° C. under reducedpressure.

Yield: 37.14 g (95%) of 6, pale-brown crystals

3-(3-Pyridinyloxy)phenylamine

a) 50 g (0.53 mol) of 3-hydroxypyridine, 178.8 g (1.05 mol) of1,3-dinitrobenzene and 159.9 g (1.16 mol) of K₂CO₃ were suspended in 1.4l of DMF, and the suspension was heated to 150° C. After the reactionmixture had been stirred at 150° C. for 16 hours, it was cooled to roomtemperature and evaporated. The residue was taken up in 1.5 l of ethylacetate, stirred for 30 minutes and filtered. The filtrate was extractedwith 10% HCl solution. The aqueous phase was rendered alkaline usingNH₄OH solution and extracted with ethyl acetate. The combined organicphases were dried using Na₂SO₄, filtered and evaporated. The residue waspurified by column chromatography (1 kg of silica gel, eluent:dichloromethane), taken up in 10% HCl solution and extracted with ethylacetate. The aqueous phase was rendered alkaline using NH₄OH solutionand extracted with ethyl acetate. The organic phase was dried usingNa₂SO₄, filtered and evaporated.

Yield: 98 g (86%) of 7, brown oil

b) Compound 7 was hydrogenated at room temperature using Pd/C inMeOH/THF. The reaction solution was filtered through kieselguhr andrinsed with MeOH, and the filtrate was subsequently evaporated. Theresidue was digested with 50 ml of diethyl ether:petroleum ether=1:1,filtered off with suction and rinsed with petroleum ether. The motherliquor was evaporated to dryness, and the residue was stored overnightin the refrigerator. The crystals formed were digested with petroleumether:diethyl ether=9:1 and filtered off with suction. The combinedcrystal batches were dried overnight at 40° C. under reduced pressure.

Yield: 77.7 g (91%) of 8, pale-brown crystals

Synthesis of the Oxalamides

N-(4-Chloro-3-trifluoromethylphenyl)-2-oxoglycine, ethyl ester

0.13 ml (1.13 mmol) of ethyl chlorooxalate was added at room temperatureto a solution of 200 mg (1.02 mmol) of 4-chloro-3-trifluoromethylanilineand 0.16 ml (1.13 mmol) of triethylamine in 2 ml of dichloromethane, andthe mixture was stirred overnight at room temperature. The reactionmixture was diluted with dichloromethane and extracted with saturatedNaCl solution. The aqueous phase was back-extracted withdichloromethane, and the combined organic phases were dried usingNa₂SO₄, filtered and evaporated.

Yield: 279 mg (92%) of 9, beige solid

N-(4-Chloro-3-trifluoromethylphenyl)-2-oxoglycine

62 mg (1.1 mmol) of potassium hydroxide were added to a solution of 270mg (0.91 mmol) of 9 in methanol, and the mixture was stirred overnightat room temperature. The reaction mixture was freeze-dried, and theresidue was taken up in water, acidified (pH 34) using 1N HCl solutionand extracted 3× with ethyl acetate. The combined organic phases weredried using Na₂SO₄, filtered and evaporated.

Yield: 219 mg (90%) of 10, beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[4-(4-pyridinyloxy)phenyl]ethanediamide

50 mg (0.19 mmol) of 10, 31.7 mg (0.17 mmol) of 2, 71 mg of TBTU (0.22mmol) and 7.8 mg (0.05 mmol) of HOBT were dissolved indimethylformamide, 0.12 ml (0.68 mmol) of N-ethyldiisopropylamine wasadded at room temperature, and the mixture was stirred overnight. Thereaction mixture was diluted with water and extracted a number of timeswith ethyl acetate. The combined organic phases were washed with water,dried using Na₂SO₄, filtered and evaporated. A little ethyl acetate andn-heptane were added to the residue, and the deposited crystals werefiltered off with suction and dried.

Yield: 26 mg (35%), beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[3-(4-pyridinyloxy)phenyl]ethanediamide

27 mg (0.10 mmol) of 10, 17.1 mg (0.09 mmol) of 4, 39 mg of TBTU (0.12mmol) and 4.3 mg (0.03 mmol) of HOBT were dissolved indimethylformamide, 0.06 ml (0.37 mmol) of N-ethyldiisopropylamine wasadded at room temperature, and the mixture was stirred overnight. Waterwas added to the reaction mixture, and the deposited crystals werefiltered off with suction, washed with diethyl ether and dried.

Yield: 7 mg (17.5%), beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[4-(3-pyridinyloxy)phenyl]ethanediamide

27 mg (0.10 mmol) of 10, 17.1 mg (0.09 mmol) of 6, 39 mg of TBTU (0.12mmol) and 4.3 mg (0.03 mmol) of HOBT were dissolved indimethylformamide, 0.06 ml (0.37 mmol) of N-ethyldiisopropylamine wasadded at room temperature, and the mixture was stirred overnight. Waterwas added to the reaction mixture, and the deposited crystals werefiltered off with suction, washed with diethyl ether and dried.

Yield: 21 mg (52.5%), beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[3-(3-pyridinyloxy)phenyl]ethanediamide

27 mg (0.10 mmol) of 10, 17.1 mg (0.09 mmol) of 8, 39 mg of TBTU (0.12mmol) and 4.3 mg (0.03 mmol) of HOBT were dissolved indimethylformamide, 0.06 ml (0.37 mmol) of N-ethyldiisopropylamine wasadded at room temperature, and the mixture was stirred overnight. Waterwas added to the reaction mixture, and the deposited crystals werefiltered off with suction, washed with diethyl ether and dried.

Yield: 6 mg (15%), beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[4-(4-pyridinylmethyl)phenyl]-ethanediamide

27 mg (0.10 mmol) of 10, 17 mg (0.09 mmol) of4-(4-pyridinylmethyl)phenylamine, 39 mg of TBTU (0.12 mmol) and 4.3 mg(0.03 mmol) of HOBT were dissolved in dimethylformamide, 0.06 ml (0.37mmol) of N-ethyldiisopropylamine was added at room temperature, and themixture was stirred overnight. Water was added to the reaction mixture,and the deposited crystals were filtered off with suction, washed withdiethyl ether and dried.

Yield: 14.5 mg (36%), beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[4-(2-methylcarbamoyl-4-pyridinyloxy)phenyl]ethandiamide

30 mg (0.11 mmol) 10, 24.8 mg (0.10 mmol)4-(4-Aminophenoxy)pyridin-2-carbonic acid, methylamide, 42.7 mg TBTU(0.13 mmol) and 4.7 mg (0.03 mmol) HOBT were dissolved indimethylformamide, 0.07 ml (0.41 mmol) of N-ethyldiisopropylamine wasadded at room temperature, and the mixture was stirred overnight. Waterwas added to the reaction mixture and then the mixture was allowed tostand for 30 min. The deposited crystals were filtered off with suction,washed with diethyl ether and purified by flash chromatography (4 gsilica gel; eluent: ethyl acetate/n-heptane.

Yield: 16 mg (31%), slightly beige solid

N-[4-Chloro-3-(trifluoromethyl)phenyl]-N′-[3-(6-methylcarbamoyl-3-pyridinyloxy)phenyl]-ethandiamide

30 mg (0.11 mmol) 10, 24.8 mg (0.10 mmol)5-(3-Aminophenoxy)pyridin-2-carbonic acid, methylamide, 42.7 mg TBTU(0.13 mmol) and 4.7 mg (0.03 mmol) HOBT were dissolved indimethylformamide, 0.07 ml (0.41 mmol) of N-ethyldiisopropylamine wasadded at room temperature, and the mixture was stirred overnight. Waterwas added to the reaction mixture and then the mixture was allowed tostand for 30 min. The deposited crystals were filtered off with suction,washed with diethyl ether and purified by flash chromatography (4 gsilica gel; eluent: ethyl acetate/n-heptane.

Yield: 24 mg (46%), slightly beige solid Retention Structure MW time(min)

435.79 2.24^(a)

435.79 2.78^(a)

435.79 2.73^(a)

435.79 2.25^(a)

433.82 2.26^(a)

492.85 5.44^(b)

492.85 5.77^(b)^(a)HPLC method:Gradient: 6 min; flow rate: 1.5 ml/min from 90:10 to 0:100 H₂O/ACNWater + TFA (0.1% by vol.); acetonitrile + TFA (0.1% by vol.)Column: Chromolith SpeedROD RP 18e 50-4.6Wavelength: 220 nm^(b)HPLC method:Gradient: 9 min; flow rate: 1.5 ml/min from 80:20 to 0:100 H₂O/ACNWater + TFA (0.01% by vol.); acetonitrile + TFA (0.01% by vol.)Column: Lichrospher RP-select-B (5 μm/125 mm)Wavelength: 220 nm

The compounds (1) to (224) as described above can preferably be producedaccording to the procedures described herein or in an analogous mannerthereof.

Example A Injection Vials

A solution of 100 g of an active compound of the formula I and 5 g ofdisodium hydrogenphosphate is adjusted to pH 6.5 in 3 l ofdouble-distilled water using 2N hydrochloric acid, sterile-filtered,dispensed into injection vials, lyophilized under sterile conditions andaseptically sealed. Each injection vial contains 5 mg of activecompound.

Example B Suppositories

A mixture of 20 g of an active compound of the formula I is fused with100 g of soya lecithin and 1400 g of cocoa butter, poured into mouldsand allowed to cool. Each suppository contains 20 mg of active compound.

Example C Solution

A solution of 1 g of an active compound of the formula I, 9.38 g ofNaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g of benzalkoniumchloride in 940 ml of double-distilled water is prepared. It is adjustedto pH 6.8, made up to 1 l and sterilized by irradiation. This solutioncan be used in the form of eye drops.

Example D Ointment

500 mg of an active compound of the formula I is mixed with 99.5 g ofpetroleum jelly under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis compressed to give tablets in a customary manner such that eachtablet contains 10 mg of active compound.

Example F Coated Tablets

Analogously to Example E, tablets are pressed and are then coated in acustomary manner using a coating of sucrose, potato starch, talc,tragacanth and colourant.

Example G Capsules

2 kg of active compound of the formula I are dispensed into hard gelatincapsules in a customary manner such that each capsule contains 20 mg ofthe active compound.

Example H Ampoules

A solution of 1 kg of active compound of the formula I in 60 l ofdouble-distilled water is sterile-filtered, dispensed into ampoules,lyophilized under sterile conditions and aseptically sealed. Eachampoule contains 10 mg of active compound.

1. Oxamide derivatives of formula IA-D-B  (I) wherein D is a bivalent oxamide moiety, or a derivativetherof, A is a unsubstituted or substituted moiety of up to 40 carbonatoms of the formula: -L-(M-L′)_(α), where L is a 5, 6 or 7 memberedcyclic structure, preferably selected from the group consisting of aryl,heteroaryl, arylene and heteroarylene, bound directly to D, L′ comprisesan optionally substituted cyclic moiety having at least 5 members,preferably selected from the group consisting of aryl, heteroaryl,aralkyl, cycloalkyl and heterocyclyl, M is a bond or a bridging grouphaving at least one atom, α is an integer of from 1-4; and each cyclicstructure of L and L′ contains 0-4 members of the group consisting ofnitrogen, oxygen and sulfur, wherein L′ is preferably substituted by atleast one substituent selected from the group consisting of—SO_(β)R_(x), —C(O)R_(x) and —C(NR_(y))R_(z) B is a substituted orunsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30carbon atoms, preferably of up to 20 carbon atoms, comprising at leastone 5-, 6-, or 7-membered cyclic structure, preferably a 5- or6-membered cyclic structure, bound directly to D containing 0-4 membersof the group consisting of nitrogen, oxygen and sulfur, wherein saidcyclic structure directly bound to D is preferably selected from thegroup consisting of aryl, heteroaryl and heterocyclyl, R_(y) is hydrogenor a carbon based moiety of up to 24 carbon atoms optionally containingheteroatoms selected from N, S and O and optionally halosubstituted, upto per halo, R_(z) is hydrogen or a carbon based moiety of up to 30carbon atoms optionally containing heteroatoms selected from N, S and Oand optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; R_(x) is R_(z), or NR_(a)R_(b), where R_(a) and R_(b) are a)independently hydrogen, a carbon based moiety of up to 30 carbon atomsoptionally containing heteroatoms selected from N, S and O andoptionally substituted by halogen, hydroxy and carbon based substituentsof up to 24 carbon atoms, which optionally contain heteroatoms selectedfrom N, S and O and are optionally substituted by halogen, or—OSi(R_(f))₃ where R_(f) is hydrogen or a carbon based moiety of up to24 carbon atoms optionally containing heteroatoms selected from N, S andO and optionally substituted by halogen, hydroxy and carbon basedsubstituents of up to 24 carbon atoms, which optionally containheteroatoms selected from N, S and O and are optionally substituted byhalogen; or b) R_(a) and R_(b) together form a 5-7 member heterocyclicstructure of 1-3 heteroatoms selected from N, S and O, or a substituted5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, Sand O substituted by halogen, hydroxy or carbon based substituents of upto 24 carbon atoms, which optionally contain heteroatoms selected fromN, S and O and are optionally substituted by halogen; or c) one of R_(a)or R_(b) is —C(O)—, a C₁-C₅ divalent alkylene group or a substitutedC₁-C₅ divalent alkylene group bound to the moiety L to form a cyclicstructure with at least 5 members, wherein the substituents of thesubstituted C₁-C₅ divalent alkylene group are selected from the groupconsisting of halogen, hydroxy, and carbon based substituents of up to24 carbon atoms, which optionally contain heteroatoms selected from N, Sand O and are optionally substituted by halogen; where B is substituted,L is substituted or L′ is additionally substituted, the substituents areselected from the group consisting of halogen, up to per-halo, and Wγ,where γ is 0-3; wherein each W is independently selected from the groupconsisting of —CN, —CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵,—SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, -Q-Ar, and carbon basedmoieties of up to 24 carbon atoms, optionally containing heteroatomsselected from N, S and O and optionally substituted by one or moresubstituents independently selected from the groups consisting of —CN,—CO₂R, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,—NR⁵C(O)OR⁵, —NR⁵C(O)R⁵ and halogen up to per-halo; with each R⁵independently selected from H or a carbon based moiety of up to 24carbon atoms, optionally containing heteroatoms selected from N, S and Oand optionally substituted by halogen, wherein Q is —O—, —S—, —N(R⁵)—,—(CH₂)_(β), —C(O)—, —CH(OH)—, —(CH₂)_(β)O—, —(CH₂)_(β)S—,—(CH₂)_(β)N(R⁵)—, —O(CH₂)_(β), —CHHal-, —CHal₂-, —S—(CH₂).— and—N(R⁵)(CH₂)_(β)— where β=1-3, and Hal is halogen; and Ar is 5- or6-member aromatic structure containing 0-2 members selected from thegroup consisting of nitrogen, oxygen and sulfur, which is optionallysubstituted by halogen, up to per-halo, and optionally substituted byZ_(δ1) wherein δ1 is 0 to 3 and each Z is independently selected fromthe group consisting —CN, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵,—SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵, —NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, and a carbon basedmoiety of up to 24 carbon atoms, optionally containing heteroatomsselected from N, S and O and optionally substituted by one or moresubstituents selected from the group consisting of —CN, —CO₂R⁵,—C(O)NR⁵R⁵, —C(O)—R⁵, —NO₂, —OR⁵, —SR⁵, —SO₂R⁵, —SO₃H, —NR⁵R⁵,—NR⁵C(O)OR⁵, —NR⁵C(O)R⁵, and the pharmaceutically acceptablederivatives, salts and solvates thereof.
 2. Oxamide derivative accordingto claim 1, characterised in that each M independently from one anotherrepresents a bond or is a bridging group, selected from the groupconsisting of (CR⁵R⁵)_(h), or (CHR⁵)_(h)-Q-(CHR⁵)_(i), wherein Q isselected from a group consisting of O, S, N—R⁵, (CHal₂)_(j),(O—CHR⁵)_(j), (CHR⁵—O)_(j), CR⁵═CR⁵, (O—CHR⁵CHR⁵)_(j), (CHR⁵CHR⁵—O)_(j),C═O, C═S, C═NR⁵, CH(OR⁵), C(OR⁵)(OR⁵), C(═O)O, OC(═O), OC(═O)O,(C═O)N(R⁵)C(═O), OC(═O)N(R⁵), N(R⁵)C(═O)O, CH═N—NR⁵, S═O, SO₂, SO₂NR⁵und NR⁵SO₂, wherein R⁵ is in each case independently selected from themeanings given above, preferably hydrogen, halogen, alkyl, aryl,aralkyl, h, i are independently from each other 0, 1, 2, 3, 4, 5, or 6,preferably 0, 1, 2 or 3, and j is 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2or
 3. 3. Oxamide derivative according to claim 1, selected from thecompounds of formula II,

wherein Ar¹, Ar² are selected independently from one another fromaromatic hydrocarbons containing 6 to 14 carbon atoms and ethylenicalunsaturated or aromatic heterocyclic residues containing 3 to 10 carbonatoms and one or two hetero atoms, independently selected from N, O undS, R⁸, R⁹ and R¹⁰ are independently selected from a group consisting ofH, A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH₂Hal, CH(Hal)₂,C(Hal)₃, NO₂, (CH₂)_(n)CN, (CH₂)_(n)NR¹¹R¹², (CH₂)_(n)OR¹¹,(CH₂)_(n)O(CH₂)_(k)NR¹¹R¹², (CH₂)_(n)COOR¹², (CH₂)_(n)CONR¹¹R¹²,(CH₂)_(n)NR¹¹COR¹³, (CH₂)_(n)NR¹¹CONR¹¹R¹², (CH₂)_(n)NR¹¹SO₂A,(CH₂)_(n)SO₂NR¹¹R¹², (CH₂)_(n)S(O)_(u)R¹³ (CH₂)_(n)OC(O)R¹³,(CH₂)_(n)COR¹³, (CH₂)_(n)SR¹¹, CH═N—OA, CH₂CH═N—OA, (CH₂)_(n)NHOA,(CH₂)_(n)CH═N—R¹¹, (CH₂)_(n)OC(O)NR¹¹R¹², (CH₂)_(n)NR¹¹COOR¹²,(CH₂)_(n)N(R¹¹)CH₂CH₂OR¹³, (CH₂)_(n)N(R¹¹)CH₂CH₂OCF₃,(CH₂)_(n)N(R¹¹)C(R¹³)HCOOR¹², C(R¹³)HCOR¹²,(CH₂)_(n)N(R¹¹)CH₂CH₂N(R¹²)CH₂COOR¹², (CH₂)_(n)N(R¹¹)CH₂CH₂NR¹¹R¹²,CH═CHCOOR¹¹, CH═CHCH₂NR¹¹R¹², CH═CHCH₂NR¹¹R¹², CH═CHCH₂OR¹³,(CH₂)_(n)N(COOR¹¹)COOR¹², (CH₂)_(n)N(CONH₂)COOR¹¹,(CH₂)_(n)N(CONH₂)CONH₂, (CH₂)_(n)N(CH₂COOR¹¹)COOR¹²,(CH₂)_(n)N(CH₂CONH₂)COOR¹¹, (CH₂)_(n)N(CH₂CONH₂)CONH₂,(CH₂)_(n)CHR¹³COR¹¹, (CH₂)_(n)CHR¹³COOR¹¹, (CH₂)_(n)CHR¹³CH₂OR¹⁴,(CH₂)_(n)OCN and (CH₂)_(n)NCO, wherein R¹¹, R¹² are independentlyselected from a group consisting of H, A, (CH₂)_(m)Ar³ and (CH₂)_(m)Het,or in NR¹¹R¹², R¹¹ and R¹² form, together with the N-Atom they are boundto, a 5-, 6- or 7-membered heterocyclus which optionally contains 1 or 2additional hetero atoms, selected from N, O an S, R¹³, R¹⁴ areindependently selected from a group consisting of H, Hal, A,(CH₂)_(m)Ar⁴ and (CH₂)_(m)Het, A is selected from the group consistingof alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy andalkoxyalkyl, Ar³, Ar⁴ are independently from one another aromatichydrocarbon residues comprising 5 to 12 and preferably 5 to 10 carbonatoms which are optionally substituted by one or more substituents,selected from a group consisting of A, Hal, NO₂, CN, OR¹⁵, NR¹⁵R¹⁶,COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵, SO₂R¹⁵R¹⁶,S(O)_(u)A and OOCR¹⁵, Het is a saturated, unsaturated or aromaticheterocyclic residue which is optionally substituted by one or moresubstituents, selected from a group consisting of A, Hal, NO₂, CN, OR¹⁵,NR¹⁵R¹⁶, COOR¹⁵, CONR¹⁵R¹⁶, NR¹⁵COR¹⁶, NR¹⁵CONR¹⁵R¹⁶, NR¹⁶SO₂A, COR¹⁵,SO₂R¹⁵R¹⁶, S(O)_(u)A and OOCR¹⁵, R¹⁵, R¹⁶ are independently selectedfrom a group consisting of H, A, and (CH₂)_(m)Ar⁵, wherein Ar⁵ is a 5-or 6-membered aromatic hydrocarbon which is optionally substituted byone or more substituents selected from a group consisting of methyl,ethyl, propyl, 2-propyl, tert.-butyl, Hal, CN, OH, NH₂ and CF₃, k, m andn are independently of one another 0, 1, 2, 3, 4, or 5; X represents abond or is (CR¹¹R¹²)_(h), or (CHR¹¹)_(h)-Q-(CHR¹²)_(i), wherein Q isselected from a group consisting of O, S, N—R¹⁵, (CHal₂)_(j),(O—CHR¹⁸)_(j), (CHR¹⁸—O)_(j), CR¹⁸═CR¹⁹, (O—CHR¹⁸CHR¹⁹)_(j),CHR¹⁸CHR¹⁹—O)_(j), C═O, C═S, C═NR¹⁵, CH(OR¹⁵), C(OR¹⁵)(OR²⁰), C(═O)O,OC(═O), OC(═O)O, C(═)N(R¹⁵), N(R¹⁵)C(═O), CH═N—O, CH═N—NR¹⁵, OC(O)NR¹⁵,NR¹⁵C(O)O, S═O, SO₂, SO₂NR¹⁵ und NR¹⁵SO₂, wherein R¹⁸, R¹⁹, R²⁰ areindependently selected from the meanings given for R⁸, R⁹ and R¹⁰, h, iare independently from each other 0, 1, 2, 3, 4, 5 or 6, and j is 1, 2,3, 4, 5 or 6, Y is selected from O, S, NR²¹, C(R²²)—NO₂, C(R²²)—CN andC(CN)₂, wherein R²¹ is independently selected from the meanings givenfor R¹³, R¹⁴, and R²² is independently selected from the meanings givenfor R”, R¹², p, r are independently from one another 0, 1, 2, 3, 4 or 5,q is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, u is 0, 1, 2 or 3,preferably 0, 1 or 2, and Hal is independently selected from a groupconsisting of F, Cl, Br and I; and the pharmaceutically acceptablederivatives, salts and solvates thereof.
 4. Oxamide derivative accordingto claim 3, selected from the compounds of formula IIa, IIb, IIc, IId,IIe, IIf, IIg and IIh,

wherein R⁶, R⁷, R⁸, p, X, Y, R⁹, q are as defined in claim 3 and R¹⁰ isH or as defined in claim 3; and the pharmaceutically acceptablederivatives, salts and solvates thereof.
 5. Oxamide derivative accordingto claim 1, selected from the compounds (1) to (224) of table 1, and thepharmaceutically acceptable derivatives, salts and solvates thereof. 6.Oxamide derivative according to claim 1 as a medicament.
 7. Oxamidederivative according to claim 1 as a kinase inhibitor.
 8. Oxamidederivative according to claim 7, characterized in that the kinases areselected from raf-kinases.
 9. Pharmaceutical composition, characterizedin that it contains one or more compounds according to claim
 1. 10.Pharmaceutical composition according to claim 9, characterised in thatit contains one or more additional compounds, selected from the groupconsisting of physiologically acceptable excipients, auxiliaries,adjuvants, carriers and pharmaceutical active ingredients other than thecompounds according to claim
 9. 11. Process for the manufacture of apharmaceutical composition, characterised in that one or more compoundsaccording to claim 1 and one or more compounds, selected from the groupconsisting of carriers, excipients, auxiliaries and pharmaceuticalactive ingredients other than the compounds according to claim 1, isprocessed by mechanical means into a pharmaceutical composition that issuitable as dosage form for application and/or administration to apatient.
 12. Use of a compound according to claim 1 as a pharmaceutical.13. Use of a compound according to claim 1 in the treatment and/orprophylaxis of disorders.
 14. Use of a compound according to claim 1 forproducing a pharmaceutical composition for the treatment and/orprophylaxis of disorders.
 15. Use according to claim 13, characterisedin that the disorders are caused, mediated and/or propagated byraf-kinases.
 16. Use according to claim 13, characterised in that thedisorders are selected from the group consisting of hyperproliferativeand nonhyperproliferative disorders.
 17. Use according to claim 13,characterised in that the disorder is cancer.
 18. Use according to claim13, characterised in that the disorder is noncancerous.
 19. Useaccording to claim 13, characterised in that the noncancerous disordersare selected from the group consisting of psioarsis, arthritis,inflammation, endometriosis, scarring, Helicobacter pylori infection,begnin prostatic hyperplasia, immunological diseases, autoimmunediseases and immunodeficiency diseases.
 20. Use according to claim 13,characterised in that the disorders are selected from the groupconsisting of melanoma, brain cancer, lung cancer, squamous cell cancer,bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer, renalcancer, colorectal cancer, breast cancer, head cancer, neck cancer,oesophageal cancer, gynaecological cancer, ovarian cancar, ovary cancer,uterine cancer, prostate cancer, thyroid cancer, lymphoma, chronicleukaemia and acute leukaemia.
 21. Use according to claim 15,characterised in that the disorders are selected from the groupconsisting of arthritis, restenosis; fibrotic disorders; mesangial cellproliferative disorders, diabetic nephropathy, malignantnephrosclerosis, thrombotic microangiopathy syndromes, organ transplantrejection, glomerulopathies, metabolic disorders, inflammation, solidtumors, rheumatic arthritis, diabetic retinopathy, and neurodegenerativediseases.
 22. Use according to claim 15, characterised in that thedisorders are selected from the group consisting of rheumatoidarthritis, inflammation, autoimmune disease, chronic obstructivepulmonary disease, asthma, inflammatory bowel disease, fibrosis,atherosclerosis, restenosis, vascular disease, cardiovascular disease,inflammation, renal disease and angiogenesis disorders.
 23. Use of acompound according to claim 1 as a raf-kinase inhibitor.
 24. Useaccording to claim 23, characterised in that the raf-kinase is selectedfrom the group consisting of A-Raf, B-Raf and c-Raf-1.
 25. Method forthe treatment and/or prophylaxis of disorders, characterised in that oneor more compounds according to claim 1 is administered to a patient inneed of such a treatment.
 26. Method according to claim 25, wherein theone or more compounds are administered as a pharmaceutical composition.27. Method for the treatment and/or prophylaxis of disorders accordingto claim 26, characterized in that the disorder is caused, medicatedand/or propagated by raf-kinase.
 28. Method for the treatment accordingto claim 27, characterised in that the disorders is cancerous cellgrowth mediated by raf-kinase.
 29. Method for producing compounds offormula II, characterised in that a) a compound of formula III

wherein L¹ is Cl, Br, I, OH, an esterified OH-group or a diazoniummoiety, and R⁸, p, Ar¹, Y are as defined in claim 3, is reacted b) witha compound of formula IV,

wherein L², L³ are independently from one another H or a metal ion, andR⁹, q, X, Ar², R¹⁰ and r are as as defined in claim 3, and optionally c)isolating and/or treating the compound of formula II obtained by saidreaction with an acid, to obtain the salt thereof.
 30. Compound offormula III,

wherein L¹ is Cl, Br, I, OH, an esterified OH-group or a diazoniummoiety, and R⁸, p, Ar¹, Y are as defined in claim
 3. 31. Compound offormula IV,

wherein L², L³ are independently from one another H or a metal ion, andR⁹, q, X, Ar², R¹⁰ and r are as defined in claim 3.